835 results on '"Miyamoto, Shigeki"'
Search Results
2. Gα12 signaling regulates transcriptional and phenotypic responses that promote glioblastoma tumor invasion
- Author
-
Chaim, Olga Meiri, Miki, Shunichiro, Prager, Briana C, Ma, Jianhui, Jeong, Anthony Y, Lara, Jacqueline, Tran, Nancy K, Smith, Jeffrey M, Rich, Jeremy N, Gutkind, J Silvio, Miyamoto, Shigeki, Furnari, Frank B, and Brown, Joan Heller
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Brain Cancer ,Biotechnology ,Rare Diseases ,Stem Cell Research ,Cancer ,Brain Disorders ,Genetics ,Neurosciences ,Humans ,Animals ,Mice ,GTP-Binding Protein alpha Subunits ,G12-G13 ,Glioblastoma ,Signal Transduction ,Neoplastic Processes ,Up-Regulation ,Cell Line ,Tumor ,Brain Neoplasms ,Cell Proliferation - Abstract
In silico interrogation of glioblastoma (GBM) in The Cancer Genome Atlas (TCGA) revealed upregulation of GNA12 (Gα12), encoding the alpha subunit of the heterotrimeric G-protein G12, concomitant with overexpression of multiple G-protein coupled receptors (GPCRs) that signal through Gα12. Glioma stem cell lines from patient-derived xenografts also showed elevated levels of Gα12. Knockdown (KD) of Gα12 was carried out in two different human GBM stem cell (GSC) lines. Tumors generated in vivo by orthotopic injection of Gα12KD GSC cells showed reduced invasiveness, without apparent changes in tumor size or survival relative to control GSC tumor-bearing mice. Transcriptional profiling of GSC-23 cell tumors revealed significant differences between WT and Gα12KD tumors including reduced expression of genes associated with the extracellular matrix, as well as decreased expression of stem cell genes and increased expression of several proneural genes. Thrombospondin-1 (THBS1), one of the genes most repressed by Gα12 knockdown, was shown to be required for Gα12-mediated cell migration in vitro and for in vivo tumor invasion. Chemogenetic activation of GSC-23 cells harboring a Gα12-coupled DREADD also increased THBS1 expression and in vitro invasion. Collectively, our findings implicate Gα12 signaling in regulation of transcriptional reprogramming that promotes invasiveness, highlighting this as a potential signaling node for therapeutic intervention.
- Published
- 2023
3. Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes
- Author
-
Torres, Alyssa, Kang, Sarah, Mahony, Christopher B, Cedeño, Martha, Oliveira, Patricia G, Fernandez-Bustamante, Marta, Kemble, Samuel, Laragione, Teresina, Gulko, Percio S, Croft, Adam P, Sanchez-Lopez, Elsa, Miyamoto, Shigeki, and Guma, Monica
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,Autoimmune Disease ,Arthritis ,Women's Health ,Rheumatoid Arthritis ,2.1 Biological and endogenous factors ,Aetiology ,Mice ,Animals ,Synoviocytes ,Hexokinase ,Arthritis ,Rheumatoid ,Synovitis ,Methotrexate ,Fibroblasts ,rheumatoid arthritis ,FLS ,mitochondria ,glucose metabolism ,hexokinase ,Immunology ,Medical Microbiology ,Biochemistry and cell biology - Abstract
BackgroundGlucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not only in the cytosol but also in the mitochondria, where it protects mitochondria against stress. We hypothesize that mitochondria-bound HK2 is a key regulator of RA FLS phenotype.MethodsHK2 localization was evaluated by confocal microscopy after FLS stimulation. RA FLSs were infected with Green fluorescent protein (GFP), full-length (FL)-HK2, or HK2 lacking its mitochondrial binding motif (HK2ΔN) expressing adenovirus (Ad). RA FLS was also incubated with methyl jasmonate (MJ; 2.5 mM), tofacitinib (1 µM), or methotrexate (1 µM). RA FLS was tested for migration and invasion and gene expression. Gene associations with HK2 expression were identified by examining single-cell RNA sequencing (scRNA-seq) data from murine models of arthritis. Mice were injected with K/BxN serum and given MJ. Ad-FLHK2 or Ad-HK2ΔN was injected into the knee of wild-type mice.ResultsCobalt chloride (CoCl2) and platelet-derived growth factor (PDGF) stimulation induced HK2 mitochondrial translocation. Overexpression of the HK2 mutant and MJ incubation reversed the invasive and migrative phenotype induced by FL-HK2 after PDGF stimulation, and MJ also decreased the expression of C-X-C Motif Chemokine Ligand 1 (CXCL1) and Collagen Type I Alpha 1 Chain (COL1A1). Of interest, tofacitinib but not methotrexate had an effect on HK2 dissociation from the mitochondria. In murine models, MJ treatment significantly decreased arthritis severity, whereas HK2FL was able to induce synovial hypertrophy as opposed to HK2ΔN.ConclusionOur results suggest that mitochondrial HK2 regulates the aggressive phenotype of RA FLS. New therapeutic approaches to dissociate HK2 from mitochondria offer a safer approach than global glycolysis inhibition.
- Published
- 2023
4. RhoA signaling increases mitophagy and protects cardiomyocytes against ischemia by stabilizing PINK1 protein and recruiting Parkin to mitochondria
- Author
-
Tu, Michelle, Tan, Valerie P, Yu, Justin D, Tripathi, Raghav, Bigham, Zahna, Barlow, Melissa, Smith, Jeffrey M, Brown, Joan Heller, and Miyamoto, Shigeki
- Subjects
Neurosciences ,Neurodegenerative ,Parkinson's Disease ,Brain Disorders ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Generic health relevance ,Humans ,Ischemia ,Mitochondria ,Mitochondrial Proteins ,Mitophagy ,Myocytes ,Cardiac ,Protein Kinases ,rhoA GTP-Binding Protein ,Ubiquitin-Protein Ligases ,Biological Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology - Abstract
Mitophagy, a mitochondria-specific form of autophagy, removes dysfunctional mitochondria and is hence an essential process contributing to mitochondrial quality control. PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin are critical molecules involved in stress-induced mitophagy, but the intracellular signaling mechanisms by which this pathway is regulated are unclear. We tested the hypothesis that signaling through RhoA, a small GTPase, induces mitophagy via modulation of the PINK1/Parkin pathway as a protective mechanism against ischemic stress. We demonstrate that expression of constitutively active RhoA as well as sphingosine-1-phosphate induced activation of endogenous RhoA in cardiomyocytes result in an accumulation of PINK1 at mitochondria. This is accompanied by translocation of Parkin to mitochondria and ubiquitination of mitochondrial proteins leading to recognition of mitochondria by autophagosomes and their lysosomal degradation. Expression of RhoA in cardiomyocytes confers protection against ischemia, and this cardioprotection is attenuated by siRNA-mediated PINK1 knockdown. In vivo myocardial infarction elicits increases in mitochondrial PINK1, Parkin, and ubiquitinated mitochondrial proteins. AAV9-mediated RhoA expression potentiates these responses and a concurrent decrease in infarct size is observed. Interestingly, induction of mitochondrial PINK1 accumulation in response to RhoA signaling is neither mediated through its transcriptional upregulation nor dependent on depolarization of the mitochondrial membrane, the canonical mechanism for PINK1 accumulation. Instead, our results reveal that RhoA signaling inhibits PINK1 cleavage, thereby stabilizing PINK1 protein at mitochondria. We further show that active RhoA localizes at mitochondria and interacts with PINK1, and that the mitochondrial localization of RhoA is regulated by its downstream effector protein kinase D. These findings demonstrate that RhoA activation engages a unique mechanism to regulate PINK1 accumulation, induce mitophagy and protect against ischemic stress, and implicates regulation of RhoA signaling as a potential strategy to enhance mitophagy and confer protection under stress conditions.
- Published
- 2022
5. A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice
- Author
-
Rajagopalan, Adhithi, Feng, Yubin, Gayatri, Meher B., Ranheim, Erik A., Klungness, Taylor, Matson, Daniel R., Lee, Moon Hee, Jung, Mabel Minji, Zhou, Yun, Gao, Xin, Nadiminti, Kalyan V.G., Yang, David T., Tran, Vu.L., Padron, Eric, Miyamoto, Shigeki, Bresnick, Emery H., and Zhang, Jing
- Subjects
Gene mutations -- Health aspects ,Gene expression -- Analysis ,RNA sequencing -- Analysis ,Hematopoietic stem cells -- Transplantation ,Health care industry - Abstract
We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in [Nras.sup.G12D/+] [p53.sup.-/-] ([NP.sup.-/- ]) mice, [Nras.sup.G120/+] [p53.sup.R172H/+] ([NP.sup.mut]) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, [NP.sup.mut] hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that oncogenic NRAS signaling and mutant p53 synergized to establish an [NP.sup.mut]-AML transcriptome distinct from that of [NP.sup.-/-] cells. The [NP.sup.mut]-AML transcriptome showed GATA2 downregulation and elevated the expression of inflammatory genes, including those linked to NF-[kappa]B signaling. NF- [kappa]B was also upregulated in human NRAS TP53 AML. Exogenous expression of GATA2 in human [NP.sup.mut] KY821 AML cells downregulated inflammatory gene expression. Mouse and human [NP.sup.mut] AML cells were sensitive to MEK and NF- [kappa]B inhibition in vitro. The proteasome inhibitor bortezomib stabilized the NF-KB-inhibitory protein iKBa, reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in [NP.sup.mut] mice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss., Introduction Acute myeloid leukemia (AML) is an aggressive and devastating hematologic malignancy characterized by the accumulation of partially differentiated myeloid blast cells ([greater than or equal to]20%) in bone marrow [...]
- Published
- 2023
- Full Text
- View/download PDF
6. HAPLN1 matrikine: a bone marrow homing factor linked to poor outcomes in patients with MM
- Author
-
Chang, Hae Yeun, Huynh, Mailee, Roopra, Avtar, Callander, Natalie S., and Miyamoto, Shigeki
- Published
- 2023
- Full Text
- View/download PDF
7. IκBα Nuclear Export Enables 4-1BB–Induced cRel Activation and IL-2 Production to Promote CD8 T Cell Immunity
- Author
-
Lisiero, Dominique N, Cheng, Zhang, Tejera, Melba M, Neldner, Brandon T, Warrick, Jay W, Wuerzberger-Davis, Shelly M, Hoffmann, Alexander, Suresh, M, and Miyamoto, Shigeki
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Vaccine Related ,Underpinning research ,1.1 Normal biological development and functioning ,Active Transport ,Cell Nucleus ,Adoptive Transfer ,Animals ,Antibodies ,Monoclonal ,CD28 Antigens ,CD8-Positive T-Lymphocytes ,Cells ,Cultured ,Interleukin-2 ,Lymphocyte Activation ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Mutation ,NF-KappaB Inhibitor alpha ,Oncogene Proteins v-rel ,Receptors ,Antigen ,T-Cell ,Signal Transduction ,Tumor Necrosis Factor Receptor Superfamily ,Member 9 ,Biochemistry and cell biology - Abstract
Optimal CD8 T cell immunity is orchestrated by signaling events initiated by TCR recognition of peptide Ag in concert with signals from molecules such as CD28 and 4-1BB. The molecular mechanisms underlying the temporal and spatial signaling dynamics in CD8 T cells remain incompletely understood. In this study, we show that stimulation of naive CD8 T cells with agonistic CD3 and CD28 Abs, mimicking TCR and costimulatory signals, coordinately induces 4-1BB and cRel to enable elevated cytosolic cRel:IκBα complex formation and subsequent 4-1BB-induced IκBα degradation, sustained cRel activation, heightened IL-2 production and T cell expansion. NfkbiaNES/NES CD8 T cells harboring a mutated IκBα nuclear export sequence abnormally accumulate inactive cRel:IκBα complexes in the nucleus following stimulation with agonistic anti-CD3 and anti-CD28 Abs, rendering them resistant to 4-1BB induced signaling and a disrupted chain of events necessary for efficient T cell expansion. Consequently, CD8 T cells in NfkbiaNES/NES mice poorly expand during viral infection, and this can be overcome by exogenous IL-2 administration. Consistent with cell-based data, adoptive transfer experiments demonstrated that the antiviral CD8 T cell defect in NfkbiaNES/NES mice was cell intrinsic. Thus, these results reveal that IκBα, via its unique nuclear export function, enables, rather than inhibits 4-1BB-induced cRel activation and IL-2 production to facilitate optimal CD8 T cell immunity.
- Published
- 2020
8. Histamine-induced biphasic activation of RhoA allows for persistent RhoA signaling.
- Author
-
Zhang, Jason, Nguyen, Andy, Miyamoto, Shigeki, Heller Brown, Joan, McCulloch, Andrew, and Zhang, Jin
- Subjects
Animals ,Calcium Signaling ,Cells ,Cultured ,Enzyme Activation ,HeLa Cells ,Histamine ,Humans ,Mice ,Phosphorylation ,Protein Kinase C ,Receptors ,Histamine ,Rho Guanine Nucleotide Exchange Factors ,Signal Transduction ,rhoA GTP-Binding Protein - Abstract
The small GTPase RhoA is a central signaling enzyme that is involved in various cellular processes such as cytoskeletal dynamics, transcription, and cell cycle progression. Many signal transduction pathways activate RhoA-for instance, Gαq-coupled Histamine 1 Receptor signaling via Gαq-dependent activation of RhoGEFs such as p63. Although multiple upstream regulators of RhoA have been identified, the temporal regulation of RhoA and the coordination of different upstream components in its regulation have not been well characterized. In this study, live-cell measurement of RhoA activation revealed a biphasic increase of RhoA activity upon histamine stimulation. We showed that the first and second phase of RhoA activity are dependent on p63 and Ca2+/PKC, respectively, and further identified phosphorylation of serine 240 on p115 RhoGEF by PKC to be the mechanistic link between PKC and RhoA. Combined approaches of computational modeling and quantitative measurement revealed that the second phase of RhoA activation is insensitive to rapid turning off of the receptor and is required for maintaining RhoA-mediated transcription after the termination of the receptor signaling. Thus, two divergent pathways enable both rapid activation and persistent signaling in receptor-mediated RhoA signaling via intricate temporal regulation.
- Published
- 2020
9. Dissociation of mitochondrial HK-II elicits mitophagy and confers cardioprotection against ischemia.
- Author
-
Tan, Valerie P, Smith, Jeffrey M, Tu, Michelle, Yu, Justin D, Ding, Eric Y, and Miyamoto, Shigeki
- Subjects
Mitochondria ,Animals ,Humans ,Rats ,Ischemia ,Hexokinase ,Mitophagy ,Biochemistry and Cell Biology ,Oncology and Carcinogenesis - Abstract
Preservation of mitochondrial integrity is critical for maintaining cellular homeostasis. Mitophagy is a mitochondria-specific type of autophagy which eliminates damaged mitochondria thereby contributing to mitochondrial quality control. Depolarization of the mitochondrial membrane potential is an established mechanism for inducing mitophagy, mediated through PINK1 stabilization and Parkin recruitment to mitochondria. Hexokinase-II (HK-II) which catalyzes the first step in glucose metabolism, also functions as a signaling molecule to regulate cell survival, and a significant fraction of cellular HK-II is associated with mitochondria (mitoHK-II). We demonstrate here that pharmacological interventions and adenoviral expression of a mitoHK-II dissociating peptide which reduce mitoHK-II levels lead to robust increases in mitochondrial Parkin and ubiquitination of mitochondrial proteins in cardiomyocytes and in a human glioblastoma cell line 1321N1, independent of mitochondrial membrane depolarization or PINK1 accumulation. MitoHK-II dissociation-induced mitophagy was demonstrated using Mito-Keima in cardiomyocytes and in 1321N1 cells. Subjecting cardiomyocytes or the in vivo heart to ischemia leads to modest dissociation of mitoHK-II. This response is potentiated by expression of the mitoHK-II dissociating peptide, which increases Parkin recruitment to mitochondria and, importantly, provides cardioprotection against ischemic stress. These results suggest that mitoHK-II dissociation is a physiologically relevant cellular event that is induced by ischemic stress, the enhancement of which protects against ischemic damage. The mechanism which underlies the effects of mitoHK-II dissociation can be attributed to the ability of Bcl2-associated athanogene 5 (BAG5), an inhibitor of Parkin, to localize to mitochondria and form a molecular complex with HK-II. Overexpression of BAG5 attenuates while knockdown of BAG5 sensitizes the effect of mitoHK-II dissociation on mitophagy. We suggest that HK-II, a glycolytic molecule, can function as a sensor for metabolic derangements at mitochondria to trigger mitophagy, and modulating the intracellular localization of HK-II could be a novel way of regulating mitophagy to prevent cell death induced by ischemic stress.
- Published
- 2019
10. The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells
- Author
-
Lee, Moon Hee, Sung, Kyung, Beebe, David, Huang, Wei, Shapiro, Dan, Miyamoto, Shigeki, and Abel, E. Jason
- Published
- 2022
- Full Text
- View/download PDF
11. Autophagy and cardiac aging
- Author
-
Miyamoto, Shigeki
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Heart Disease ,Aging ,Cardiovascular ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Aetiology ,Underpinning research ,Good Health and Well Being ,Animals ,Autophagy ,Autophagy-Related Proteins ,Cardiovascular Diseases ,Cellular Senescence ,Humans ,Inflammasomes ,Mitochondrial Dynamics ,Reactive Oxygen Species ,Signal Transduction ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Cardiovascular disease (CVD) is the leading cause of death and the prevalence of CVD dramatically increases with age. Cardiac aging is associated with hypertrophy, fibrosis, inflammation, and decreased contractility. Autophagy, a bulk degradation/recycling system, is essential to maintain cellular homeostasis. Cardiac autophagy is decreased with age, and misfolded proteins and dysfunctional mitochondria are accumulated in the aging heart. Inhibition of autophagy leads to exacerbated cardiac aging, while stimulation of autophagy improves cardiac function and also increases lifespan in many organisms. Thus autophagy represents a potential therapeutic target for aging-related cardiac dysfunction. This review discusses recent progress in our understanding of the role and regulation of autophagy in the aging heart.
- Published
- 2019
12. Yes-associated protein (YAP) mediates adaptive cardiac hypertrophy in response to pressure overload
- Author
-
Byun, Jaemin, Del Re, Dominic P, Zhai, Peiyong, Ikeda, Shohei, Shirakabe, Akihiro, Mizushima, Wataru, Miyamoto, Shigeki, Brown, Joan H, and Sadoshima, Junichi
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Cardiovascular ,Heart Disease ,Heart Disease - Coronary Heart Disease ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Adaptor Proteins ,Signal Transducing ,Animals ,Apoptosis ,Cardiomegaly ,Cell Cycle ,Cell Cycle Proteins ,Down-Regulation ,Fibrosis ,Gene Knockout Techniques ,Heterozygote ,Mice ,Mice ,Inbred C57BL ,Myocytes ,Cardiac ,PTEN Phosphohydrolase ,Phosphoproteins ,Pressure ,Proto-Oncogene Proteins c-akt ,YAP-Signaling Proteins ,rhoA GTP-Binding Protein ,cardiac hypertrophy ,signal transduction ,cardiomyocyte ,cardiovascular disease ,heart failure ,YAP ,Chemical Sciences ,Biological Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
Cardiovascular disease (CVD) remains the leading cause of death globally, and heart failure is a major component of CVD-related morbidity and mortality. The development of cardiac hypertrophy in response to hemodynamic overload is initially considered to be beneficial; however, this adaptive response is limited and, in the presence of prolonged stress, will transition to heart failure. Yes-associated protein (YAP), the central downstream effector of the Hippo signaling pathway, regulates proliferation and survival in mammalian cells. Our previous work demonstrated that cardiac-specific loss of YAP leads to increased cardiomyocyte (CM) apoptosis and impaired CM hypertrophy during chronic myocardial infarction (MI) in the mouse heart. Because of its documented cardioprotective effects, we sought to determine the importance of YAP in response to acute pressure overload (PO). Our results indicate that endogenous YAP is activated in the heart during acute PO. YAP activation that depended upon RhoA was also observed in CMs subjected to cyclic stretch. To examine the function of endogenous YAP during acute PO, Yap+/flox;Creα-MHC (YAP-CHKO) and Yap+/flox mice were subjected to transverse aortic constriction (TAC). We found that YAP-CHKO mice had attenuated cardiac hypertrophy and significant increases in CM apoptosis and fibrosis that correlated with worsened cardiac function after 1 week of TAC. Loss of CM YAP also impaired activation of the cardioprotective kinase Akt, which may underlie the YAP-CHKO phenotype. Together, these data indicate a prohypertrophic, prosurvival function of endogenous YAP and suggest a critical role for CM YAP in the adaptive response to acute PO.
- Published
- 2019
13. Fibroblast-Like Synoviocytes Glucose Metabolism as a Therapeutic Target in Rheumatoid Arthritis
- Author
-
de Oliveira, Patricia Gnieslaw, Farinon, Mirian, Sanchez-Lopez, Elsa, Miyamoto, Shigeki, and Guma, Monica
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Arthritis ,Clinical Research ,Rheumatoid Arthritis ,Autoimmune Disease ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Musculoskeletal ,Animals ,Arthritis ,Rheumatoid ,Fibroblasts ,Glucose ,Humans ,Osteoarthritis ,Synoviocytes ,rheumatoid arthritis ,fibroblast-like synoviocytes ,hexokinase-2 ,glucose metabolism ,glycolytic inhibitors ,Immunology ,Medical Microbiology ,Biochemistry and cell biology ,Genetics - Abstract
Metabolomic studies show that rheumatoid arthritis (RA) is associated with metabolic disruption that may be therapeutically targetable. Among them, glucose metabolism and glycolytic intermediaries seem to have an important role in fibroblast-like synoviocytes (FLS) phenotype and might contribute to early stage disease pathogenesis. RA FLS are transformed from quiescent to aggressive and metabolically active cells and several works have shown that glucose metabolism is increased in activated FLS. Glycolytic inhibitors reduce not only FLS aggressive phenotype in vitro but also decrease bone and cartilage damage in several murine models of arthritis. Essential glycolytic enzymes, including hexokinase 2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) enzymes, have important roles in FLS behavior. Of interest, HK2 is an inducible enzyme present only in the inflamed rheumatic tissues compared to osteoarthritis synovium. It is a contributor to glucose metabolism that could be selectively targeted without compromising systemic homeostasis as a novel approach for combination therapy independent of systemic immunosuppression. More information about metabolic targets that do not compromise global glucose metabolism in normal cells is needed.
- Published
- 2019
14. Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca2+/Calmodulin-Dependent Protein Kinase II δ Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling
- Author
-
Suetomi, Takeshi, Willeford, Andrew, Brand, Cameron S, Cho, Yoshitake, Ross, Robert S, Miyamoto, Shigeki, and Brown, Joan Heller
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Heart Disease - Coronary Heart Disease ,Heart Disease ,Genetics ,Cardiovascular ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Apoptosis ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Chemokines ,Cytokines ,Female ,Fibrosis ,Heart Failure ,Inflammasomes ,Inflammation ,Macrophages ,Male ,Mice ,Mice ,Knockout ,Myocytes ,Cardiac ,NF-kappa B ,NLR Family ,Pyrin Domain-Containing 3 Protein ,Reactive Oxygen Species ,Signal Transduction ,Ventricular Remodeling ,calcium-calmodulin-dependent ,inflammasomes ,inflammation ,protein kinases ,ventricular remodeling ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Public Health and Health Services ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences ,Sports science and exercise - Abstract
BackgroundInflammation is associated with cardiac remodeling and heart failure, but how it is initiated in response to nonischemic interventions in the absence of cell death is not known. We tested the hypothesis that activation of Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) in cardiomyocytes (CMs) in response to pressure overload elicits inflammatory responses leading to adverse remodeling.MethodsMice in which CaMKIIδ was selectively deleted from CMs (cardiac-specific knockout [CKO]) and floxed control mice were subjected to transverse aortic constriction (TAC). The effects of CM-specific CaMKIIδ deletion on inflammatory gene expression, inflammasome activation, macrophage accumulation, and fibrosis were assessed by quantitative polymerase chain reaction, histochemistry, and ventricular remodeling by echocardiography.ResultsTAC induced increases in cardiac mRNA levels for proinflammatory chemokines and cytokines in ≤3 days, and these responses were significantly blunted when CM CaMKIIδ was deleted. Apoptotic and necrotic cell death were absent at this time. CMs isolated from TAC hearts mirrored these robust increases in gene expression, which were markedly attenuated in CKO. Priming and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome, assessed by measuring interleukin-1β and NOD-like receptor pyrin domain-containing protein 3 mRNA levels, caspase-1 activity, and interleukin-18 cleavage, were increased at day 3 after TAC in control hearts and in CMs isolated from these hearts. These responses were dependent on CaMKIIδ and associated with activation of Nuclear Factor-kappa B and reactive oxygen species. Accumulation of macrophages observed at days 7 to 14 after TAC was diminished in CKO and, by blocking Monocyte Chemotactic Protein-1 signaling, deletion of CM Monocyte Chemotactic Protein-1 or inhibition of inflammasome activation. Fibrosis was also attenuated by these interventions and in the CKO heart. Ventricular dilation and contractile dysfunction observed at day 42 after TAC were diminished in the CKO. Inhibition of CaMKII, Nuclear Factor-kappa B, inflammasome, or Monocyte Chemotactic Protein-1 signaling in the first 1 or 2 weeks after TAC decreased remodeling, but inhibition of CaMKII after 2 weeks did not.ConclusionsActivation of CaMKIIδ in response to pressure overload triggers inflammatory gene expression and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome in CMs. These responses provide signals for macrophage recruitment, fibrosis, and myocardial dysfunction in the heart. Our work suggests the importance of targeting early inflammatory responses induced by CM CaMKIIδ signaling to prevent progression to heart failure.
- Published
- 2018
15. Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis.
- Author
-
Bustamante, Marta F, Oliveira, Patricia G, Garcia-Carbonell, Ricard, Croft, Adam P, Smith, Jeff M, Serrano, Ramon L, Sanchez-Lopez, Elsa, Liu, Xiao, Kisseleva, Tatiana, Hay, Nissim, Buckley, Christopher D, Firestein, Gary S, Murphy, Anne N, Miyamoto, Shigeki, and Guma, Monica
- Subjects
Synovial Membrane ,Animals ,Mice ,Transgenic ,Humans ,Arthritis ,Experimental ,Arthritis ,Rheumatoid ,Osteoarthritis ,Synovitis ,Hexokinase ,RNA ,Small Interfering ,Inflammation Mediators ,Cell Movement ,Gene Expression Regulation ,Synoviocytes ,autoimmune diseases ,fibroblasts ,inflammation ,rheumatoid arthritis ,Autoimmune Disease ,Aging ,Arthritis ,Aetiology ,2.1 Biological and endogenous factors ,Musculoskeletal ,Inflammatory and immune system ,Clinical Sciences ,Immunology ,Public Health and Health Services ,Arthritis & Rheumatology - Abstract
ObjectivesRecent studies indicate that glucose metabolism is altered in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Hexokinases (HKs) catalyse the first step in glucose metabolism, and HK2 constitutes the principal HK inducible isoform. We hypothesise that HK2 contributes to the synovial lining hypertrophy and plays a critical role in bone and cartilage damage.MethodsHK1 and HK2 expression were determined in RA and osteoarthritis (OA) synovial tissue by immunohistochemistry. RA FLS were transfected with either HK1 or HK2 siRNA, or infected with either adenovirus (ad)-GFP, ad-HK1 or ad-HK2. FLS migration and invasion were assessed. To study the role of HK2 in vivo, 108 particles of ad-HK2 or ad-GFP were injected into the knee of wild-type mice. K/BxN serum transfer arthritis was induced in HK2F/F mice harbouring Col1a1-Cre (HK2Col1), to delete HK2 in non-haematopoietic cells.ResultsHK2 is particular of RA histopathology (9/9 RA; 1/8 OA) and colocalises with FLS markers. Silencing HK2 in RA FLS resulted in a less invasive and migratory phenotype. Consistently, overexpression of HK2 resulted in an increased ability to migrate and invade. It also increased extracellular lactate production. Intra-articular injection of ad-HK2 in normal knees dramatically increased synovial lining thickness, FLS activation and proliferation. HK2 was highly expressed in the synovial lining after K/BxN serum transfer arthritis. HK2Col1 mice significantly showed decreased arthritis severity, bone and cartilage damage.ConclusionHK2 is specifically expressed in RA synovial lining and regulates FLS aggressive functions. HK2 might be an attractive selective metabolic target safer than global glycolysis for RA treatment.
- Published
- 2018
16. RhoA regulates Drp1 mediated mitochondrial fission through ROCK to protect cardiomyocytes
- Author
-
Brand, Cameron S, Tan, Valerie P, Brown, Joan Heller, and Miyamoto, Shigeki
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Heart Disease ,Cardiovascular ,5.1 Pharmaceuticals ,1.1 Normal biological development and functioning ,Development of treatments and therapeutic interventions ,Underpinning research ,Animals ,Cell Death ,Dynamins ,Lysophospholipids ,Mitochondria ,Heart ,Mitochondrial Dynamics ,Myocytes ,Cardiac ,Oxidative Stress ,Phosphorylation ,Rats ,Rats ,Sprague-Dawley ,Signal Transduction ,Sphingosine ,rho GTP-Binding Proteins ,rho-Associated Kinases ,rhoA GTP-Binding Protein ,RhoA ,Sphingosine-1-phosphate ,Drp1 ,Mitochondria ,Fission ,Cardioprotection ,Medical Physiology ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
Cardiac ischemia/reperfusion, loss of blood flow and its subsequent restoration, causes damage to the heart. Oxidative stress from ischemia/reperfusion leads to dysfunction and death of cardiomyocytes, increasing the risk of progression to heart failure. Alterations in mitochondrial dynamics, in particular mitochondrial fission, have been suggested to play a role in cardioprotection from oxidative stress. We tested the hypothesis that activation of RhoA regulates mitochondrial fission in cardiomyocytes. Our studies show that expression of constitutively active RhoA in cardiomyocytes increases phosphorylation of Dynamin-related protein 1 (Drp1) at serine-616, and leads to localization of Drp1 at mitochondria. Both responses are blocked by inhibition of Rho-associated Protein Kinase (ROCK). Endogenous RhoA activation by the GPCR agonist sphingosine-1-phosphate (S1P) also increases Drp1 phosphorylation and its mitochondrial translocation in a RhoA and ROCK dependent manner. Consistent with the role of mitochondrial Drp1 in fission, RhoA activation in cardiomyocytes leads to formation of smaller mitochondria and this is attenuated by inhibition of ROCK, by siRNA knockdown of Drp1 or by expression of a phosphorylation-deficient Drp1 S616A mutant. In addition, activation of RhoA prevents cell death in cardiomyocytes challenged by oxidative stress and this protection is blocked by siRNA knockdown of Drp1 or by Drp1 S616A expression. Taken together our findings demonstrate that RhoA activation can regulate Drp1 to induce mitochondrial fission and subsequent cellular protection, implicating regulation of fission as a novel mechanism contributing to RhoA-mediated cardioprotection.
- Published
- 2018
17. YAP and MRTF-A, transcriptional co-activators of RhoA-mediated gene expression, are critical for glioblastoma tumorigenicity
- Author
-
Yu, Olivia M, Benitez, Jorge A, Plouffe, Steven W, Ryback, Daniel, Klein, Andrea, Smith, Jeff, Greenbaum, Jason, Delatte, Benjamin, Rao, Anjana, Guan, Kun-Liang, Furnari, Frank B, Chaim, Olga Meiri, Miyamoto, Shigeki, and Brown, Joan Heller
- Subjects
Cancer ,Neurosciences ,Brain Disorders ,Biotechnology ,Brain Cancer ,Genetics ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Adaptor Proteins ,Signal Transducing ,Animals ,Brain Neoplasms ,Gene Expression Regulation ,Neoplastic ,Glioblastoma ,Heterografts ,Humans ,Mice ,Mice ,Nude ,Phosphoproteins ,Trans-Activators ,Transcription Factors ,YAP-Signaling Proteins ,rhoA GTP-Binding Protein ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors and were of lower morbidity than wild-type cells. In vitro studies used PDX and 1321N1 glioblastoma cells to examine functional responses to sphingosine 1-phosphate (S1P), a GPCR agonist that activates RhoA signaling, demonstrated that YAP signaling was required for cell migration and invasion, whereas MRTF-A was required for cell adhesion; both YAP and MRTF-A were required for proliferation. Gene expression analysis by RNA-sequencing of S1P-treated MRTF-A or YAP knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor (TF)), a target gene regulated selectively through YAP, blocked cell invasion and migration, whereas knockdown of HBEGF (heparin-binding epidermal growth factor-like growth factor), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of target genes regulated through either or both YAP and MRTF-A. Expression of TF and HBEGF was also selectively decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in preclinical GBM models and suggesting that their activation through GPCRs and RhoA contributes to growth and maintenance of human GBM.
- Published
- 2018
18. CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis
- Author
-
Willeford, Andrew, Suetomi, Takeshi, Nickle, Audrey, Hoffman, Hal M, Miyamoto, Shigeki, and Brown, Joan Heller
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Heart Disease ,Cardiovascular ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Angiotensin II ,Animals ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Cell Death ,Chemokine CCL2 ,Chemokines ,Cytokines ,Fibrosis ,Gene Deletion ,Gene Expression ,Inflammasomes ,Inflammation ,Macrophages ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Muscle Cells ,Myocytes ,Cardiac ,NF-kappa B ,NLR Family ,Pyrin Domain-Containing 3 Protein ,RNA ,Messenger ,Signal Transduction ,Cardiology ,Cardiovascular disease ,Biomedical and clinical sciences ,Health sciences - Abstract
Inflammation accompanies heart failure and is a mediator of cardiac fibrosis. CaMKIIδ plays an essential role in adverse remodeling and decompensation to heart failure. We postulated that inflammation is the mechanism by which CaMKIIδ contributes to adverse remodeling in response to nonischemic interventions. We demonstrate that deletion of CaMKIIδ in the cardiomyocyte (CKO) significantly attenuates activation of NF-κB, expression of inflammatory chemokines and cytokines, and macrophage accumulation induced by angiotensin II (Ang II) infusion. The inflammasome was activated by Ang II, and this response was also diminished in CKO mice. These events occurred prior to any evidence of Ang II-induced cell death. In addition, CaMKII-dependent inflammatory gene expression and inflammasome priming were observed as early as the third hour of infusion, a time point at which macrophage recruitment was not evident. Inhibition of either the inflammasome or monocyte chemoattractant protein 1 (MCP1) signaling attenuated macrophage accumulation, and these interventions, like cardiomyocyte CaMKIIδ deletion, diminished the fibrotic response to Ang II. Thus, activation of CaMKIIδ in the cardiomyocyte represents what we believe to be a novel mechanism for initiating inflammasome activation and an inflammatory gene program that leads to macrophage recruitment and ultimately to development of fibrosis.
- Published
- 2018
19. CaMKII delta subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-kappa B and TNF-alpha
- Author
-
Gray, Charles BB, Suetomi, Takeshi, Xiang, Sunny, Mishra, Shikha, Blackwood, Erik A, Glembotski, Christopher C, Miyamoto, Shigeki, Westenbrink, B Daan, and Brown, Joan Heller
- Subjects
CaMKII ,NF-kappa B ,TNF-alpha ,Ischemia/reperfusion ,Heart ,Cardiovascular System & Hematology ,Cardiorespiratory Medicine and Haematology - Published
- 2017
20. CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α.
- Author
-
Gray, Charles BB, Suetomi, Takeshi, Xiang, Sunny, Mishra, Shikha, Blackwood, Erik A, Glembotski, Christopher C, Miyamoto, Shigeki, Westenbrink, B Daan, and Brown, Joan Heller
- Subjects
Myocardium ,Myocytes ,Cardiac ,Animals ,Mice ,Transgenic ,Mice ,Rats ,Myocardial Reperfusion Injury ,Myocardial Infarction ,Ventricular Dysfunction ,Disease Models ,Animal ,Tumor Necrosis Factor-alpha ,NF-kappa B ,Echocardiography ,Biopsy ,Signal Transduction ,Phosphorylation ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Gene Knockout Techniques ,CaMKII ,Heart ,Inflammation ,Ischemia/reperfusion ,NF-κB ,Signal transduction ,TNF-α ,Myocytes ,Cardiac ,Transgenic ,Disease Models ,Animal ,Cardiovascular System & Hematology ,Cardiorespiratory Medicine and Haematology ,Medical Physiology - Abstract
Deletion of Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKIIδ isoforms and downstream mechanisms are responsible for the salutary effects of CaMKIIδ gene deletion. In this study we sought to compare the roles of the CaMKIIδB and CaMKIIδC subtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKIIδKO, and mice expressing only CaMKIIδB or δC were subjected to ex vivo global ischemia for 25min followed by reperfusion. Infarct formation was assessed at 60min reperfusion by triphenyl tetrazolium chloride (TTC) staining. Deletion of CaMKIIδ conferred significant protection from ex vivo I/R. Re-expression of CaMKIIδC in the CaMKIIδKO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKIIδB was protective. Selective activation of CaMKIIδC in response to I/R was evident in a subcellular fraction enriched for cytosolic/membrane proteins. Further studies demonstrated differential regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and tumor necrosis factor alpha (TNF-α) expression by CaMKIIδB and CaMKIIδC. Selective activation of CaMKIIδC was also observed and associated with NF-κB activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-κB or TNF-α significantly ameliorated infarct formation in WT mice and those that re-express CaMKIIδC, demonstrating distinct roles for CaMKIIδ subtypes in I/R and implicating acute activation of CaMKIIδC and NF-κB in the pathogenesis of reperfusion injury.
- Published
- 2017
21. Selective coupling of the S1P3 receptor subtype to S1P-mediated RhoA activation and cardioprotection
- Author
-
Yung, Bryan S, Brand, Cameron S, Xiang, Sunny Y, Gray, Charles BB, Means, Christopher K, Rosen, Hugh, Chun, Jerold, Purcell, Nicole H, Brown, Joan Heller, and Miyamoto, Shigeki
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Heart Disease ,Heart Disease - Coronary Heart Disease ,Cardiovascular ,Animals ,Cardiomegaly ,Lysophospholipids ,Male ,Mice ,Myocardial Reperfusion Injury ,Myocardium ,Myocytes ,Cardiac ,Proprotein Convertases ,Protein Binding ,Rats ,Receptors ,Lysosphingolipid ,Serine Endopeptidases ,Signal Transduction ,Sphingosine ,TRPP Cation Channels ,rhoA GTP-Binding Protein ,Sphingosine-1-phosphate ,G protein-coupled receptor ,Ras homolog gene family member A ,Protein kinase D ,Phospholipase C ,Ischemia/reperfusion ,Cardioprotection ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Biochemistry and cell biology ,Cardiovascular medicine and haematology ,Medical physiology - Abstract
Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P1, S1P2, and S1P3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to Gq. We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD. The S1P receptor subtypes and G proteins that regulate RhoA activation and downstream responses in the heart have not been determined. Using siRNA or pertussis toxin to inhibit different G proteins in NRVMs we established that S1P regulates RhoA activation through Gα13 but not Gα12, Gαq, or Gαi. Knockdown of the three major S1P receptors using siRNA demonstrated a requirement for S1P3 in RhoA activation and subsequent phosphorylation of PKD, and this was confirmed in studies using isolated hearts from S1P3 knockout (KO) mice. S1P treatment reduced infarct size induced by ischemia/reperfusion in Langendorff perfused wild-type (WT) hearts and this protection was abolished in the S1P3 KO mouse heart. CYM-51736, an S1P3-specific agonist, also decreased infarct size after ischemia/reperfusion to a degree similar to that achieved by S1P. The finding that S1P3 receptor- and Gα13-mediated RhoA activation is responsible for protection against ischemia/reperfusion suggests that selective targeting of S1P3 receptors could provide therapeutic benefits in ischemic heart disease.
- Published
- 2017
22. Nutrient-sensing mTORC1: Integration of metabolic and autophagic signals
- Author
-
Tan, Valerie P and Miyamoto, Shigeki
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Nutrition ,Heart Disease ,Cardiovascular ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Animals ,Autophagy ,Carrier Proteins ,Energy Metabolism ,Humans ,Mechanistic Target of Rapamycin Complex 1 ,Multiprotein Complexes ,Myocardium ,Oxidation-Reduction ,Protein Binding ,Signal Transduction ,TOR Serine-Threonine Kinases ,mTORC1 ,Amino acids ,Glucose ,Hypoxia ,Metabolism ,Cardiorespiratory Medicine and Haematology ,Medical Physiology ,Cardiovascular System & Hematology ,Biochemistry and cell biology ,Cardiovascular medicine and haematology ,Medical physiology - Abstract
The ability of adult cardiomyocytes to regenerate is limited, and irreversible loss by cell death plays a crucial role in heart diseases. Autophagy is an evolutionarily conserved cellular catabolic process through which long-lived proteins and damaged organelles are targeted for lysosomal degradation. Autophagy is important in cardiac homeostasis and can serve as a protective mechanism by providing an energy source, especially in the face of sustained starvation. Cellular metabolism is closely associated with cell survival, and recent evidence suggests that metabolic and autophagic signaling pathways exhibit a high degree of crosstalk and are functionally interdependent. In this review, we discuss recent progress in our understanding of regulation of autophagy and its crosstalk with metabolic signaling, with a focus on the nutrient-sensing mTOR complex 1 (mTORC1) pathway.
- Published
- 2016
23. Drp1 and Mitochondrial Autophagy Lend a Helping Hand in Adaptation to Pressure Overload
- Author
-
Miyamoto, Shigeki and Brown, Joan Heller
- Subjects
Animals ,Autophagy ,Dynamins ,Heart Failure ,Humans ,Mitochondria ,heart failure ,Editorials ,pressure overload ,mitochondria ,autophagy ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Public Health and Health Services ,Cardiovascular System & Hematology - Published
- 2016
24. Myocardin-Related Transcription Factor A and Yes-Associated Protein Exert Dual Control in G Protein-Coupled Receptor- and RhoA-Mediated Transcriptional Regulation and Cell Proliferation
- Author
-
Yu, Olivia M, Miyamoto, Shigeki, and Brown, Joan Heller
- Subjects
Cancer ,Genetics ,Underpinning research ,2.1 Biological and endogenous factors ,Aetiology ,1.1 Normal biological development and functioning ,Generic health relevance ,Adaptor Proteins ,Signal Transducing ,Cell Proliferation ,Cells ,Cultured ,Cysteine-Rich Protein 61 ,Gene Expression Regulation ,Humans ,Phosphoproteins ,Promoter Regions ,Genetic ,Receptors ,G-Protein-Coupled ,Serum Response Factor ,Trans-Activators ,Transcription Factors ,Transcription ,Genetic ,YAP-Signaling Proteins ,rhoA GTP-Binding Protein ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
The ability of a subset of G protein-coupled receptors (GPCRs) to activate RhoA endows them with unique growth-regulatory properties. Two transcriptional pathways are activated through GPCRs and RhoA, one utilizing the transcriptional coactivator myocardin-related transcription factor A (MRTF-A) and serum response factor (SRF) and the other using the transcriptional coactivator Yes-associated protein (YAP) and TEA domain family members (TEAD). These pathways have not been compared for their relative levels of importance and potential interactions in RhoA target gene expression. GPCRs for thrombin and sphingosine-1-phosphate (S1P) on human glioblastoma cells robustly couple to RhoA and induce the matricelluar protein CCN1. Knockdown of either MRTF-A or YAP abrogates S1P-stimulated CCN1 expression, demonstrating that both coactivators are required. MRTF-A and YAP are also both required for transcriptional control of other S1P-regulated genes in various cell types and for S1P-stimulated glioblastoma cell proliferation. Interactions between MRTF-A and YAP are suggested by their synergistic effects on SRE.L- and TEAD-luciferase expression. Moreover, MRTF-A and YAP associate in coimmunoprecipitations from S1P-stimulated cells. Chromatin immunoprecipitation (ChIP) analysis of the CCN1 gene promoter demonstrated that S1P increases coactivator binding at the canonical transcription factor sequences. Unexpectedly, S1P also enhances MRTF-A binding at TEA sites. Our findings reveal that GPCR- and RhoA-regulated gene expression requires dual input and integration of two distinct transcriptional pathways.
- Published
- 2016
25. Correction for Romero et al., “Pseudorabies Virus Infection Results in a Broad Inhibition of Host Gene Transcription”
- Author
-
Romero, Nicolás, primary, Wuerzberger-Davis, Shelly M., additional, Van Waesberghe, Cliff, additional, Jansens, Robert J., additional, Tishchenko, Alexander, additional, Verhamme, Ruth, additional, Miyamoto, Shigeki, additional, and Favoreel, Herman W., additional
- Published
- 2023
- Full Text
- View/download PDF
26. Analyze the SUMOylation of IKKγ/NEMO During Genotoxic Stress
- Author
-
Wu, Zhao-Hui, primary and Miyamoto, Shigeki, additional
- Published
- 2021
- Full Text
- View/download PDF
27. Mitochondrial Reprogramming Induced by CaMKII&dgr; Mediates Hypertrophy Decompensation
- Author
-
Westenbrink, B Daan, Ling, Haiyun, Divakaruni, Ajit S, Gray, Charles BB, Zambon, Alexander C, Dalton, Nancy D, Peterson, Kirk L, Gu, Yusu, Matkovich, Scot J, Murphy, Anne N, Miyamoto, Shigeki, Dorn, Gerald W, and Heller Brown, Joan
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Genetics ,Heart Disease ,Cardiovascular ,Aetiology ,2.1 Biological and endogenous factors ,Acetylcysteine ,Animals ,Apoptosis ,Benzylamines ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Cardiomegaly ,Cardiomyopathy ,Dilated ,Cells ,Cultured ,Disease Progression ,GTP-Binding Protein alpha Subunits ,Gq-G11 ,Gene Expression Profiling ,Heart Failure ,Ion Channels ,Male ,Mice ,Mice ,Knockout ,Mice ,Transgenic ,Mitochondria ,Heart ,Mitochondrial Proteins ,Myocytes ,Cardiac ,Oxidative Stress ,PPAR alpha ,Point Mutation ,Pressure ,RNA Interference ,RNA ,Messenger ,RNA ,Small Interfering ,Rats ,Reactive Oxygen Species ,Sequence Analysis ,RNA ,Sulfonamides ,Transfection ,Uncoupling Protein 3 ,calcium-calmodulin-dependent protein kinase type 2 ,G-protein ,Gq ,heart failure ,mitochondrial uncoupling protein 3 ,oxidative stress ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences - Abstract
RationaleSustained activation of Gαq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca(2+)/calmodulin-dependent protein kinase II δ (CaMKIIδ) is activated downstream of Gq, and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation.ObjectiveTo determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq.Methods and resultsCompared with Gq mice, compound Gq/CaMKIIδ knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKIIδ deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of ≈40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIδ deletion or inhibition, as was peroxisome proliferator-activated receptor α. The protective effects of CaMKIIδ inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor α and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIδ deletion.ConclusionsMitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.
- Published
- 2015
28. Nonequilibrium Reactivation of Na+ Current Drives Early Afterdepolarizations in Mouse Ventricle
- Author
-
Edwards, Andrew G, Grandi, Eleonora, Hake, Johan E, Patel, Sonia, Li, Pan, Miyamoto, Shigeki, Omens, Jeffrey H, Heller Brown, Joan, Bers, Donald M, and McCulloch, Andrew D
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Heart Disease ,Cardiovascular ,2.1 Biological and endogenous factors ,Aetiology ,Action Potentials ,Adrenergic beta-Antagonists ,Animals ,Calcium ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Computer Simulation ,Female ,Heart Ventricles ,Male ,Mice ,Transgenic ,Models ,Cardiovascular ,Myocytes ,Cardiac ,Sarcoplasmic Reticulum ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,Sodium ,Sodium Channel Blockers ,Sodium-Calcium Exchanger ,Time Factors ,Ventricular Function ,arrhythmias ,cardiac ,calcium/ calmodulin-dependent protein kinase type 2 ,electrophysiology ,sodium-calcium exchanger 1 ,arrhythmias ,calcium/calmodulin-dependent protein kinase type 2 ,cardiac ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences ,Medical physiology - Abstract
BackgroundEarly afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca(2+) current (ICaL) reactivation or sarcoplasmic reticulum Ca(2+) release and Na(+)/Ca(2+) exchange. In large mammals the positive action potential plateau promotes ICaL reactivation, and the current paradigm holds that cardiac EAD dynamics are dominated by interaction between ICaL and the repolarizing K(+) currents. However, EADs are also frequent in the rapidly repolarizing mouse action potential, which should not readily permit ICaL reactivation. This suggests that murine EADs exhibit unique dynamics, which are key for interpreting arrhythmia mechanisms in this ubiquitous model organism. We investigated these dynamics in myocytes from arrhythmia-susceptible calcium calmodulin-dependent protein kinase II delta C (CaMKIIδC)-overexpressing mice (Tg), and via computational simulations.Methods and resultsIn Tg myocytes, β-adrenergic challenge slowed late repolarization, potentiated sarcoplasmic reticulum Ca(2+) release, and initiated EADs below the ICaL activation range (-47 ± 0.7 mV). These EADs were abolished by caffeine and tetrodotoxin (but not ranolazine), suggesting that sarcoplasmic reticulum Ca(2+) release and Na(+) current (INa), but not late INa, are required for EAD initiation. Simulations suggest that potentiated sarcoplasmic reticulum Ca(2+) release and Na(+)/Ca(2+) exchange shape late action potential repolarization to favor nonequilibrium reactivation of INa and thereby drive the EAD upstroke. Action potential clamp experiments suggest that lidocaine eliminates virtually all inward current elicited by EADs, and that this effect occurs at concentrations (40-60 μmol/L) for which lidocaine remains specific for inactivated Na(+) channels. This strongly suggests that previously inactive channels are recruited during the EAD upstroke, and that nonequilibrium INa dynamics underlie murine EADs.ConclusionsNonequilibrium reactivation of INa drives murine EADs.
- Published
- 2014
29. Induction of the matricellular protein CCN1 through RhoA and MRTF-A contributes to ischemic cardioprotection
- Author
-
Zhao, Xia, Ding, Eric Y, Yu, Olivia M, Xiang, Sunny Y, Tan-Sah, Valerie P, Yung, Bryan S, Hedgpeth, Joe, Neubig, Richard R, Lau, Lester F, Brown, Joan Heller, and Miyamoto, Shigeki
- Subjects
Biochemistry and Cell Biology ,Medical Physiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Heart Disease ,Heart Disease - Coronary Heart Disease ,Cardiovascular ,5.1 Pharmaceuticals ,Animals ,Animals ,Newborn ,Cardiotonic Agents ,Cell Membrane ,Cell Nucleus ,Cysteine-Rich Protein 61 ,Heart Ventricles ,In Vitro Techniques ,Lysophospholipids ,Mice ,Knockout ,Models ,Biological ,Myocardial Ischemia ,Myocytes ,Cardiac ,Protein Binding ,RNA ,Small Interfering ,Rats ,Rats ,Sprague-Dawley ,Receptors ,G-Protein-Coupled ,Reperfusion Injury ,Sphingosine ,Transcription Factors ,rhoA GTP-Binding Protein ,CCN1 ,RhoA ,MRTF-A ,GPCRs ,Cardioprotection ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Biochemistry and cell biology ,Cardiovascular medicine and haematology ,Medical physiology - Abstract
Activation of RhoA, a low molecular-weight G-protein, plays an important role in protecting the heart against ischemic stress. Studies using non-cardiac cells demonstrate that the expression and subsequent secretion of the matricellular protein CCN1 is induced by GPCR agonists that activate RhoA. In this study we determined whether and how CCN1 is induced by GPCR agonists in cardiomyocytes and examined the role of CCN1 in ischemic cardioprotection in cardiomyocytes and the isolated perfused heart. In neonatal rat ventricular myocytes (NRVMs), sphingosine 1-phosphate (S1P), lysophosphatidic acid (LPA) and endothelin-1 induced robust increases in CCN1 expression while phenylephrine, isoproterenol and carbachol had little or no effect. The ability of agonists to activate the small G-protein RhoA correlated with their ability to induce CCN1. CCN1 induction by S1P was blocked when RhoA function was inhibited with C3 exoenzyme or a pharmacological RhoA inhibitor. Conversely overexpression of RhoA was sufficient to induce CCN1 expression. To delineate the signals downstream of RhoA we tested the role of MRTF-A (MKL1), a co-activator of SRF, in S1P-mediated CCN1 expression. S1P increased the nuclear accumulation of MRTF-A and this was inhibited by the functional inactivation of RhoA. In addition, pharmacological inhibitors of MRTF-A or knockdown of MRTF-A significantly diminished S1P-mediated CCN1 expression, indicating a requirement for RhoA/MRTF-A signaling. We also present data indicating that CCN1 is secreted following agonist treatment and RhoA activation, and binds to cells where it can serve an autocrine function. To determine the functional significance of CCN1 expression and signaling, simulated ischemia/reperfusion (sI/R)-induced apoptosis was assessed in NRVMs. The ability of S1P to protect against sI/R was significantly reduced by the inhibition of RhoA, ROCK or MRTF-A or by CCN1 knockdown. We also demonstrate that ischemia/reperfusion induces CCN1 expression in the isolated perfused heart and that this functions as a cardioprotective mechanism, evidenced by the significant increase in infarct development in response to I/R in the cardiac specific CCN1 KO relative to control mice. Our findings implicate CCN1 as a mediator of cardioprotection induced by GPCR agonists that activate RhoA/MRTF-A signaling.
- Published
- 2014
30. Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition.
- Author
-
Roberts, David J, Tan-Sah, Valerie P, Ding, Eric Y, Smith, Jeffery M, and Miyamoto, Shigeki
- Subjects
Cells ,Cultured ,Myocytes ,Cardiac ,Animals ,Rats ,Multiprotein Complexes ,Hexokinase ,Glucose ,Glucose-6-Phosphate ,RNA ,Small Interfering ,Immunoprecipitation ,Food Deprivation ,Gene Expression Regulation ,Enzymologic ,Amino Acid Motifs ,Oxidative Stress ,Phosphorylation ,Mutation ,Autophagy ,TOR Serine-Threonine Kinases ,Mechanistic Target of Rapamycin Complex 1 ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Hexokinase-II (HK-II) catalyzes the first step of glycolysis and also functions as a protective molecule; however, its role in protective autophagy has not been determined. Results showed that inhibition of HK-II diminished, while overexpression of HK-II potentiated, autophagy induced by glucose deprivation in cardiomyocyte and noncardiomyocyte cells. Immunoprecipitation studies revealed that HK-II binds to and inhibits the autophagy suppressor, mTOR complex 1 (TORC1), and that this binding was increased by glucose deprivation. The TOS motif, a scaffold sequence responsible for binding TORC1 substrates, is present in HK-II, and mutating it blocked its ability to bind to TORC1 and regulate protective autophagy. The transition from glycolysis to autophagy appears to be regulated by a decrease in glucose-6 phosphate. We suggest that HK-II binds TORC1 as a decoy substrate and provides a previously unrecognized mechanism for switching cells from a metabolic economy, based on plentiful energy, to one of conservation, under starvation.
- Published
- 2014
31. HAPLN1 matrikine: A bone marrow homing factor linked to poor MM patient outcomes
- Author
-
Chang, Hae Yeun, primary, Huynh, Mailee, additional, Roopra, Avtar Singh, additional, Callander, Natalie S, additional, and Miyamoto, Shigeki, additional
- Published
- 2023
- Full Text
- View/download PDF
32. Several Alphaherpesviruses Interact Similarly with the NF-κB Pathway and Suppress NF-κB-Dependent Gene Expression
- Author
-
Romero, Nicolás, primary, Tishchenko, Alexander, additional, Verhamme, Ruth, additional, Wuerzberger-Davis, Shelly M., additional, Van Waesberghe, Cliff, additional, Nauwynck, Hans J., additional, Miyamoto, Shigeki, additional, and Favoreel, Herman W., additional
- Published
- 2023
- Full Text
- View/download PDF
33. Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes
- Author
-
Torres, Alyssa, primary, Kang, Sarah, additional, Mahony, Christopher B., additional, Cedeño, Martha, additional, Oliveira, Patricia G., additional, Fernandez-Bustamante, Marta, additional, Kemble, Samuel, additional, Laragione, Teresina, additional, Gulko, Percio S., additional, Croft, Adam P., additional, Sanchez-Lopez, Elsa, additional, Miyamoto, Shigeki, additional, and Guma, Monica, additional
- Published
- 2023
- Full Text
- View/download PDF
34. PLCε, PKD1, and SSH1L Transduce RhoA Signaling to Protect Mitochondria from Oxidative Stress in the Heart
- Author
-
Xiang, Sunny Y, Ouyang, Kunfu, Yung, Bryan S, Miyamoto, Shigeki, Smrcka, Alan V, Chen, Ju, and Brown, Joan Heller
- Subjects
Heart Disease ,Cardiovascular ,Animals ,Cofilin 2 ,Hydrogen Peroxide ,Lysophospholipids ,Mice ,Mitochondria ,Heart ,Oxidative Stress ,Phosphoinositide Phospholipase C ,Phosphoprotein Phosphatases ,Protein Kinase C ,Protein Transport ,Signal Transduction ,Sphingosine ,bcl-2-Associated X Protein ,rhoA GTP-Binding Protein ,Biochemistry and Cell Biology - Abstract
Activation of the small guanosine triphosphatase RhoA can promote cell survival in cultured cardiomyocytes and in the heart. We showed that the circulating lysophospholipid sphingosine 1-phosphate (S1P), a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) agonist, signaled through RhoA and phospholipase Cε (PLCε) to increase the phosphorylation and activation of protein kinase D1 (PKD1). Genetic deletion of either PKD1 or its upstream regulator PLCε inhibited S1P-mediated cardioprotection against ischemia/reperfusion injury. Cardioprotection involved PKD1-mediated phosphorylation and inhibition of the cofilin phosphatase Slingshot 1L (SSH1L). Cofilin 2 translocates to mitochondria in response to oxidative stress or ischemia/reperfusion injury, and both S1P pretreatment and SSH1L knockdown attenuated translocation of cofilin 2 to mitochondria. Cofilin 2 associates with the proapoptotic protein Bax, and the mitochondrial translocation of Bax in response to oxidative stress was also attenuated by S1P treatment in isolated hearts or by knockdown of SSH1L or cofilin 2 in cardiomyocytes. Furthermore, SSH1L knockdown, like S1P treatment, increased cardiomyocyte survival and preserved mitochondrial integrity after oxidative stress. These findings reveal a pathway initiated by GPCR agonist-induced RhoA activation, in which PLCε signals to PKD1-mediated phosphorylation of cytoskeletal proteins to prevent the mitochondrial translocation and proapoptotic function of cofilin 2 and Bax and thereby promote cell survival.
- Published
- 2013
35. Chromatin-Bound IκBα Regulates a Subset of Polycomb Target Genes in Differentiation and Cancer
- Author
-
Mulero, María Carmen, Ferres-Marco, Dolors, Islam, Abul, Margalef, Pol, Pecoraro, Matteo, Toll, Agustí, Drechsel, Nils, Charneco, Cristina, Davis, Shelly, Bellora, Nicolás, Gallardo, Fernando, López-Arribillaga, Erika, Asensio-Juan, Elena, Rodilla, Verónica, González, Jessica, Iglesias, Mar, Shih, Vincent, Albà, M Mar, Di Croce, Luciano, Hoffmann, Alexander, Miyamoto, Shigeki, Villà-Freixa, Jordi, López-Bigas, Nuria, Keyes, William M, Domínguez, María, Bigas, Anna, and Espinosa, Lluís
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Cancer ,Genetics ,Animals ,Cell Differentiation ,Cell Nucleus ,Cell Transformation ,Neoplastic ,Chromatin ,HEK293 Cells ,Histones ,Humans ,I-kappa B Proteins ,Keratinocytes ,Mice ,Mice ,Inbred C57BL ,NF-KappaB Inhibitor alpha ,Signal Transduction ,Skin Neoplasms ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
IκB proteins are the primary inhibitors of NF-κB. Here, we demonstrate that sumoylated and phosphorylated IκBα accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IκBα modulates Polycomb recruitment and imparts their competence to be activated by TNFα. Mutations in the Drosophila IκBα gene cactus enhance the homeotic phenotype of Polycomb mutants, which is not counteracted by mutations in dorsal/NF-κB. Oncogenic transformation of keratinocytes results in cytoplasmic IκBα translocation associated with a massive activation of Hox. Accumulation of cytoplasmic IκBα was found in squamous cell carcinoma (SCC) associated with IKK activation and HOX upregulation.
- Published
- 2013
36. Molecular Linkage between the Kinase ATM and NF-κB Signaling in Response to Genotoxic Stimuli
- Author
-
Wu, Zhao-Hui, Shi, Yuling, Tibbetts, Randal S., and Miyamoto, Shigeki
- Published
- 2006
37. Revisited and Revised: Is RhoA Always a Villain in Cardiac Pathophysiology?
- Author
-
Miyamoto, Shigeki, Del Re, Dominic P., Xiang, Sunny Y., Zhao, Xia, Florholmen, Geir, and Brown, Joan Heller
- Subjects
Medicine & Public Health ,Medicine/Public Health, general ,Biomedicine general ,Biomedical Engineering ,Human Genetics ,Cardiology ,RhoA ,Cardiomyocyte Ischemia ,ROCK - Abstract
The neonatal rat ventricular myocyte model of hypertrophy has provided tremendous insight with regard to signaling pathways regulating cardiac growth and gene expression. Many mediators thus discovered have been successfully extrapolated to the in vivo setting, as assessed using genetically engineered mice and physiological interventions. Studies in neonatal rat ventricular myocytes demonstrated a role for the small G-protein RhoA and its downstream effector kinase, Rho-associated coiled-coil containing protein kinase (ROCK), in agonist-mediated hypertrophy. Transgenic expression of RhoA in the heart does not phenocopy this response, however, nor does genetic deletion of ROCK prevent hypertrophy. Pharmacologic inhibition of ROCK has effects most consistent with roles for RhoA signaling in the development of heart failure or responses to ischemic damage. Whether signals elicited downstream of RhoA promote cell death or survival and are deleterious or salutary is, however, context and cell-type dependent. The concepts discussed above are reviewed, and the hypothesis that RhoA might protect cardiomyocytes from ischemia and other insults is presented. Novel RhoA targets including phospholipid regulated and regulating enzymes (Akt, PI kinases, phospholipase C, protein kinases C and D) and serum response element-mediated transcriptional responses are considered as possible pathways through which RhoA could affect cardiomyocyte survival.
- Published
- 2010
38. Akt mediated mitochondrial protection in the heart: metabolic and survival pathways to the rescue
- Author
-
Miyamoto, Shigeki, Murphy, Anne N., and Brown, Joan Heller
- Subjects
Chemistry ,Organic Chemistry ,Animal Biochemistry ,Animal Anatomy / Morphology / Histology ,Biochemistry, general ,Bioorganic Chemistry ,Akt ,Mitochondria ,Heart ,Hexokinase-II - Abstract
Cardiomyocyte death is now recognized as a critical factor in the development of heart disease. Mitochondria are not only responsible for energy production to ensure that cardiac output meets the body’s energy demands, but they serve as critical integrators of cell survival signals. Numerous stressors are known to induce cell death by necrosis and/or apoptosis mediated through mitochondrial dysregulation. Anti- and pro-apoptotic Bcl-2 family proteins regulate apoptosis by controlling mitochondrial outer membrane permeability, whereas opening of the mitochondrial permeability transition pore (PT-pore) induces large amplitude permeability of the inner membrane and consequent rupture of the outer membrane. Akt is one of the best described survival kinases activated by receptor ligands and its activation preserves mitochondrial integrity and protects cardiomyocytes against necrotic and apoptotic death. The mechanisms responsible for Akt-mediated mitochondrial protection have not been fully elucidated. There is, however, accumulating evidence that multiple Akt target molecules, recruited through both transcriptional and post-transcriptional mechanisms, directly impinge upon and protect mitochondria. In this review we discuss mechanisms by which Akt activation can effect changes at the mitochondria that protect cardiomyocytes and attenuate pathophysiological responses of the heart.
- Published
- 2009
39. Supplementary Figure from A Hyaluronan and Proteoglycan Link Protein 1 Matrikine: Role of Matrix Metalloproteinase 2 in Multiple Myeloma NF-κB Activation and Drug Resistance
- Author
-
Mark, Christina, primary, Warrick, Jay, primary, Callander, Natalie S., primary, Hematti, Peiman, primary, and Miyamoto, Shigeki, primary
- Published
- 2023
- Full Text
- View/download PDF
40. Data from A Hyaluronan and Proteoglycan Link Protein 1 Matrikine: Role of Matrix Metalloproteinase 2 in Multiple Myeloma NF-κB Activation and Drug Resistance
- Author
-
Mark, Christina, primary, Warrick, Jay, primary, Callander, Natalie S., primary, Hematti, Peiman, primary, and Miyamoto, Shigeki, primary
- Published
- 2023
- Full Text
- View/download PDF
41. Supplemental Tables 1 - 2, Figures 1 - 3 from Tumoricidal Effects of Macrophage-Activating Immunotherapy in a Murine Model of Relapsed/Refractory Multiple Myeloma
- Author
-
Jensen, Jeffrey Lee, primary, Rakhmilevich, Alexander, primary, Heninger, Erika, primary, Broman, Aimee Teo, primary, Hope, Chelsea, primary, Phan, Funita, primary, Miyamoto, Shigeki, primary, Maroulakou, Ioanna, primary, Callander, Natalie, primary, Hematti, Peiman, primary, Chesi, Marta, primary, Bergsagel, P. Leif, primary, Sondel, Paul, primary, and Asimakopoulos, Fotis, primary
- Published
- 2023
- Full Text
- View/download PDF
42. Supplementary Figure S1 from Bortezomib-Resistant Nuclear Factor-κB Activity in Multiple Myeloma Cells
- Author
-
Markovina, Stephanie, primary, Callander, Natalie S., primary, O'Connor, Shelby L., primary, Kim, Jihoon, primary, Werndli, Jae E., primary, Raschko, Martha, primary, Leith, Catherine P., primary, Kahl, Brad S., primary, Kim, KyungMann, primary, and Miyamoto, Shigeki, primary
- Published
- 2023
- Full Text
- View/download PDF
43. Data from Tumoricidal Effects of Macrophage-Activating Immunotherapy in a Murine Model of Relapsed/Refractory Multiple Myeloma
- Author
-
Jensen, Jeffrey Lee, primary, Rakhmilevich, Alexander, primary, Heninger, Erika, primary, Broman, Aimee Teo, primary, Hope, Chelsea, primary, Phan, Funita, primary, Miyamoto, Shigeki, primary, Maroulakou, Ioanna, primary, Callander, Natalie, primary, Hematti, Peiman, primary, Chesi, Marta, primary, Bergsagel, P. Leif, primary, Sondel, Paul, primary, and Asimakopoulos, Fotis, primary
- Published
- 2023
- Full Text
- View/download PDF
44. Data from Bortezomib-Resistant Nuclear Factor-κB Activity in Multiple Myeloma Cells
- Author
-
Markovina, Stephanie, primary, Callander, Natalie S., primary, O'Connor, Shelby L., primary, Kim, Jihoon, primary, Werndli, Jae E., primary, Raschko, Martha, primary, Leith, Catherine P., primary, Kahl, Brad S., primary, Kim, KyungMann, primary, and Miyamoto, Shigeki, primary
- Published
- 2023
- Full Text
- View/download PDF
45. Supplementary Figures 1-3 from NFKB1 Is a Direct Target of the TAL1 Oncoprotein in Human T Leukemia Cells
- Author
-
Chang, Pei-Yun, primary, Draheim, Kyle, primary, Kelliher, Michelle A., primary, and Miyamoto, Shigeki, primary
- Published
- 2023
- Full Text
- View/download PDF
46. CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α
- Author
-
Gray, Charles B.B., Suetomi, Takeshi, Xiang, Sunny, Mishra, Shikha, Blackwood, Erik A., Glembotski, Christopher C., Miyamoto, Shigeki, Westenbrink, B. Daan, and Brown, Joan Heller
- Published
- 2017
- Full Text
- View/download PDF
47. Selective coupling of the S1P3 receptor subtype to S1P-mediated RhoA activation and cardioprotection
- Author
-
Yung, Bryan S., Brand, Cameron S., Xiang, Sunny Y., Gray, Charles B.B., Means, Christopher K., Rosen, Hugh, Chun, Jerold, Purcell, Nicole H., Brown, Joan Heller, and Miyamoto, Shigeki
- Published
- 2017
- Full Text
- View/download PDF
48. Cytoplasmic Catalytic Subunit of Protein Kinase A Mediates Cross-Repression by NF-κ B and the Glucocorticoid Receptor
- Author
-
Doucas, Vassilis, Shi, Yanhong, Miyamoto, Shigeki, West, Andrew, Verma, Inder, and Evans, Ronald M.
- Published
- 2000
49. A Nuclear Export Signal in the N-Terminal Regulatory Domain of Iκ Bα Controls Cytoplasmic Localization of Inactive NF-κ B/Iκ Bα Complexes
- Author
-
Huang, Tony T., Kudo, Nobuaki, Yoshida, Minoru, and Miyamoto, Shigeki
- Published
- 2000
50. Hippo signaling pathway and mitochondrial dysfunction in takotsubo syndrome
- Author
-
Miyamoto, Shigeki, primary
- Published
- 2023
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.