12 results on '"Sashida, Goro"'
Search Results
2. Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia.
- Author
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Tanaka S, Miyagi S, Sashida G, Chiba T, Yuan J, Mochizuki-Kashio M, Suzuki Y, Sugano S, Nakaseko C, Yokote K, Koseki H, and Iwama A
- Subjects
- Animals, Cells, Cultured, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Down-Regulation genetics, Enhancer of Zeste Homolog 2 Protein, Gene Deletion, HEK293 Cells, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Polycomb Repressive Complex 2, Transcription Factors genetics, Transcription Factors metabolism, Up-Regulation genetics, Cell Differentiation genetics, Cell Transformation, Neoplastic genetics, DNA-Binding Proteins physiology, Leukemia, Myeloid, Acute genetics, Transcription Factors physiology
- Abstract
EZH2, a catalytic component of the polycomb repressive complex 2, trimethylates histone H3 at lysine 27 (H3K27) to repress the transcription of target genes. Although EZH2 is overexpressed in various cancers, including some hematologic malignancies, the role of EZH2 in acute myeloid leukemia (AML) has yet to be examined in vivo. In the present study, we transformed granulocyte macrophage progenitors from Cre-ERT;Ezh2(flox/flox) mice with the MLL-AF9 leukemic fusion gene to analyze the function of Ezh2 in AML. Deletion of Ezh2 in transformed granulocyte macrophage progenitors compromised growth severely in vitro and attenuated the progression of AML significantly in vivo. Ezh2-deficient leukemic cells developed into a chronic myelomonocytic leukemia-like disease with a lower frequency of leukemia-initiating cells compared with the control. Chromatin immunoprecipitation followed by sequencing revealed a significant reduction in the levels of trimethylation at H3K27 in Ezh2-deficient leukemic cells, not only at Cdkn2a, a known major target of Ezh2, but also at a cohort of genes relevant to the developmental and differentiation processes. Overexpression of Egr1, one of the derepressed genes in Ezh2-deficient leukemic cells, promoted the differentiation of AML cells profoundly. Our findings suggest that Ezh2 inhibits differentiation programs in leukemic stem cells, thereby augmenting their leukemogenic activity.
- Published
- 2012
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3. The mef/elf4 transcription factor fine tunes the DNA damage response.
- Author
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Sashida G, Bae N, Di Giandomenico S, Asai T, Gurvich N, Bazzoli E, Liu Y, Huang G, Zhao X, Menendez S, and Nimer SD
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins metabolism, DNA genetics, DNA metabolism, DNA radiation effects, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, DNA-Binding Proteins radiation effects, Enzyme Activation, Gamma Rays, HEK293 Cells, Histones metabolism, Humans, Mice, Mice, Knockout, NIH 3T3 Cells, Phosphorylation radiation effects, Protein Serine-Threonine Kinases metabolism, Transcription Factors deficiency, Transcription Factors genetics, Transcription Factors radiation effects, Tumor Suppressor Proteins metabolism, DNA Breaks, Double-Stranded, DNA-Binding Proteins metabolism, Transcription Factors metabolism
- Abstract
The ATM kinase plays a critical role in initiating the DNA damage response that is triggered by genotoxic stresses capable of inducing DNA double-strand breaks. Here, we show that ELF4/MEF, a member of the ETS family of transcription factors, contributes to the persistence of γH2AX DNA damage foci and promotes the DNA damage response leading to the induction of apoptosis. Conversely, the absence of ELF4 promotes the faster repair of damaged DNA and more rapid disappearance of γH2AX foci in response to γ-irradiation, leading to a radio-resistant phenotype despite normal ATM phosphorylation. Following γ-irradiation, ATM phosphorylates ELF4, leading to its degradation; a mutant form of ELF4 that cannot be phosphorylated by ATM persists following γ-irradiation, delaying the resolution of γH2AX foci and triggering an excessive DNA damage response. Thus, although ELF4 promotes the phosphorylation of H2AX by ATM, its activity must be dampened by ATM-dependent phosphorylation and degradation to avoid an excessive DNA damage response., (©2011 AACR.)
- Published
- 2011
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- View/download PDF
4. The oncogenic role of the ETS transcription factors MEF and ERG.
- Author
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Sashida G, Bazzoli E, Menendez S, Liu Y, and Nimer SD
- Subjects
- DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Humans, Proto-Oncogene Proteins c-ets genetics, Proto-Oncogene Proteins c-ets metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Trans-Activators genetics, Trans-Activators metabolism, Transcription Factors genetics, Transcription Factors metabolism, Transcriptional Regulator ERG, Tumor Suppressor Protein p53 metabolism, ras Proteins metabolism, DNA-Binding Proteins physiology, Neoplasms metabolism, Proto-Oncogene Proteins c-ets physiology, Trans-Activators physiology, Transcription Factors physiology
- Abstract
Several ETS transcription factors, including MEF/ELF4 and ERG, can function as oncogenes and are overexpressed in human cancer. MEF cooperates in tumorigenesis in retroviral insertional mutagenesis-based mouse models of cancer and MEF is overexpressed in human lymphoma and ovarian cancer tissues via unknown mechanisms. ERG (Ets related gene) overexpression or increased activity has been found in various human cancers, including sarcomas, acute myeloid leukemia and prostate cancer, where the ERG gene is rearranged due to chromosomal translocations. We have been examining how MEF functions as an oncogene and recently showed that MEF can cooperate with H-Ras(G12V) and can inhibit both p53 and p16 expression thereby promoting transformation. In fact, in cells lacking p53, the absence of Mef abrogates H-Ras(G12V)-induced transformation of mouse embryonic fibroblasts, at least in part due to increased p16 expression. We discuss the known mechanisms by which the ETS transcription factors MEF and ERG contribute to the malignant transformation of cells.
- Published
- 2010
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5. ELF4/MEF activates MDM2 expression and blocks oncogene-induced p16 activation to promote transformation.
- Author
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Sashida G, Liu Y, Elf S, Miyata Y, Ohyashiki K, Izumi M, Menendez S, and Nimer SD
- Subjects
- Animals, Cells, Cultured, Cellular Senescence physiology, Cyclin-Dependent Kinase Inhibitor p16 genetics, DNA-Binding Proteins genetics, Fibroblasts cytology, Fibroblasts physiology, Gene Expression Regulation, Genes, ras, Humans, Mice, Mice, Knockout, Nuclear Proteins genetics, Nuclear Proteins metabolism, Polycomb Repressive Complex 1, Promoter Regions, Genetic, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2 genetics, Repressor Proteins genetics, Repressor Proteins metabolism, Survival Rate, Transcription Factors genetics, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p16 metabolism, DNA-Binding Proteins metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Transcription Factors metabolism
- Abstract
Several ETS transcription factors, including ELF4/MEF, can function as oncogenes in murine cancer models and are overexpressed in human cancer. We found that Elf4/Mef activates Mdm2 expression; thus, lack of or knockdown of Elf4/Mef reduces Mdm2 levels in mouse embryonic fibroblasts (mef's), leading to enhanced p53 protein accumulation and p53-dependent senescence. Even though p53 is absent in Elf4(-/-) p53(-/-) mef's, neither oncogenic H-Ras(V12) nor c-myc can induce transformation of these cells. This appears to relate to the INK4a/ARF locus; both p19(ARF) and p16 are increased in Elf4(-/-) p53(-/-) mef's, and expression of Bmi-1 or knockdown of p16 in this context restores H-Ras(V12)-induced transformation. Thus, ELF4/MEF promotes tumorigenesis by inhibiting both the p53 and p16/Rb pathways.
- Published
- 2009
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6. Cryptic chromosomal anomaly in a patient with acute myeloid leukemia leading to AML1/ETO fusion with unfavorable prognostic factors.
- Author
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Ishii Y, Sashida G, Takaku TI, Sumi M, Nakajima A, and Ohyashiki K
- Subjects
- Core Binding Factor Alpha 2 Subunit, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Prognosis, RUNX1 Translocation Partner 1 Protein, Chromosome Aberrations, Leukemia, Myeloid, Acute genetics, Oncogene Proteins, Fusion genetics, Transcription Factors genetics
- Published
- 2005
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7. Variant translocation t(2;21;8)(q36;q22;q22) with RUNX1/CBFA2T1 (AML1/ETO) transcript in a case of acute myelogenous leukemia.
- Author
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Hsiao HH, Sashida G, Kodama A, Fukutake K, and Ohyashiki K
- Subjects
- Core Binding Factor Alpha 2 Subunit, Humans, Male, Middle Aged, RUNX1 Translocation Partner 1 Protein, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Genetic Variation, Leukemia, Myeloid, Acute genetics, Oncogene Proteins, Fusion genetics, Transcription Factors genetics, Translocation, Genetic
- Published
- 2005
- Full Text
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8. Chromatin modifier Hmga2 promotes adult hematopoietic stem cell function and blood regeneration in stress conditions.
- Author
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Kubota, Sho, Sun, Yuqi, Morii, Mariko, Bai, Jie, Ideue, Takako, Hirayama, Mayumi, Sorin, Supannika, Eerdunduleng, Yokomizo-Nakano, Takako, Osato, Motomi, Hamashima, Ai, Iimori, Mihoko, Araki, Kimi, Umemoto, Terumasa, and Sashida, Goro
- Subjects
HEMATOPOIETIC stem cells ,CELL physiology ,TRANSCRIPTION factors ,PROTEIN kinase CK2 ,BLOOD cells ,HEMATOPOIESIS ,CHROMATIN - Abstract
The molecular mechanisms governing the response of hematopoietic stem cells (HSCs) to stress insults remain poorly defined. Here, we investigated effects of conditional knock-out or overexpression of Hmga2 (High mobility group AT-hook 2), a transcriptional activator of stem cell genes in fetal HSCs. While Hmga2 overexpression did not affect adult hematopoiesis under homeostasis, it accelerated HSC expansion in response to injection with 5-fluorouracil (5-FU) or in vitro treatment with TNF-α. In contrast, HSC and megakaryocyte progenitor cell numbers were decreased in Hmga2 KO animals. Transcription of inflammatory genes was repressed in Hmga2 -overexpressing mice injected with 5-FU, and Hmga2 bound to distinct regions and chromatin accessibility was decreased in HSCs upon stress. Mechanistically, we found that casein kinase 2 (CK2) phosphorylates the Hmga2 acidic domain, promoting its access and binding to chromatin, transcription of anti-inflammatory target genes, and the expansion of HSCs under stress conditions. Notably, the identified stress-regulated Hmga2 gene signature is activated in hematopoietic stem progenitor cells of human myelodysplastic syndrome patients. In sum, these results reveal a TNF-α/CK2/phospho-Hmga2 axis controlling adult stress hematopoiesis. Synopsis: The molecular mechanisms controlling the response of hematopoietic stem cells (HSCs) to insults remain poorly defined. Here, genetic data support a critical role of chromatin modifier Hmga2 in stress-induced regeneration of the adult murine blood system. Conditional depletion of Hmga2 does not affect steady-state hematopoiesis but impairs HSC response to 5-fluorouracil (5-FU) in adult mice. Under stress, CK2 kinase phosphorylates Hmga2 in TNF-α-dependent manner, promoting its chromatin binding and repression of inflammatory genes by transcription factor Rfx5. The identified stress-induced Hmga2 gene signature is activated in hematopoietic stem and progenitor cells of human myelodysplastic syndrome patients. A TNF-a/CK2/phospho-HMGA2 axis controls chromatin accessibility, transcription, and expansion of blood stem cells in response to stress. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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9. p53 Regulates Hematopoietic Stem Cell Quiescence.
- Author
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Yan Liu, Elf, Shannon E., Miyata, Yasuhiko, Sashida, Goro, Yuhui Liu, Gang Huang, Di Giandomenico, Silvana, Lee, Jennifer M., Deblasio, Anthony, Menendez, Silvia, Antipin, Jack, Reva, Boris, Koff, Andrew, and Nimer, Stephen D.
- Subjects
P53 protein ,HEMATOPOIETIC stem cells ,DNA damage ,TRANSCRIPTION factors ,GENE expression - Abstract
The importance of the p53 protein in the cellular response to DNA damage is well known, but its function during steady-state hematopoiesis has not been established. We have defined a critical role of p53 in regulating hematopoietic stem cell quiescence, especially in promoting the enhanced quiescence seen in HSCs that lack the MEF/ELF4 transcription factor. Transcription profiling of HSCs isolated from wild-type and p53 null mice identified Gfi-1 and Necdin as p53 target genes, and using lentiviral vectors to upregulate or knockdown the expression of these genes, we show their importance in regulating HSC quiescence. Establishing the role of p53 (and its target genes) in controlling the cell-cycle entry of HSCs may lead to therapeutic strategies capable of eliminating quiescent cancer (stem) cells. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
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10. EZH2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an EZH1-depenedent manner.
- Author
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Mochizuki-Kashio, Makiko, Sashida, Goro, Aoyama, Kazumasa, Wang, Changshan, Tomioka, Takahisa, Oshima, Motohiko, and Iwama, Atsushi
- Subjects
- *
HEMATOPOIESIS , *TRANSCRIPTION factors , *HEMATOPOIETIC stem cells , *HEMATOPOIETIC system , *BONE marrow , *HEMATOLOGY - Published
- 2015
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11. Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator.
- Author
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Kameda, Takuro, Shide, Kotaro, Yamaji, Takumi, Kamiunten, Ayako, Sekine, Masaaki, Taniguchi, Yasuhiro, Hidaka, Tomonori, Yoko Kubuki, Shimoda, Haruko, Marutsuka, Kousuke, Sashida, Goro, Aoyama, Kazumasa, Yoshimitsu, Makoto, Harada, Taku, Hiroo Abe, Miike, Tadashi, Iwakiri, Hisayoshi, Tahara, Yoshihiro, Sueta, Mitsue, and Yamamoto, Shojiro
- Subjects
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MYELOPROLIFERATIVE neoplasms , *GENETIC mutation , *HEMATOPOIESIS , *GENE expression , *TRANSCRIPTION factors - Abstract
Acquired mutations of JAK2 and TET2 are frequent in myeloproliferative neoplasms (MPNs). We examined the individual and cooperative effects of these mutations on MPN development. Recipients of JAK2V617F cells developed primary myelofibrosis-like features; the addition of loss-of-TET2 worsened this JAK2V617F-induced disease, causing prolonged leukocytosis, splenomegaly, extramedullary hematopoiesis, and modestly shorter survival. Double mutant (JAK2V617F and loss-of-TET2) myeloid cells were more likely to be in a proliferative state than JAK2V617F single mutant myeloid cells. In a serial competitive transplantation assay, JAK2V617F cells resulted in decreased chimerism in the 2nd recipients, which did not develop MPNs. In marked contrast, cooperation between JAK2V617F and loss-of-TET2 developed and maintained MPNs in the 2nd recipients by compensating for impaired hematopoietic stem cell (HSC) functioning. In vitro sequential colony formation assays also supported the observation that JAK2V617F did not maintain HSC functioning over the long term, but concurrent loss-of-TET2 mutation restored it. Transcriptional profiling revealed that loss-of-TET2 affected the expression of many HSC signature genes. We conclude that loss-of-TET2 has two different roles in MPNs; one is as a disease accelerator, while the other is as a disease initiator and sustainer in combination with JAK2V617F. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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12. The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations.
- Author
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Gang Huang, Xinghui Zhao, Lan Wang, Elf, Shannon, Hao Xu, Xinyang Zhao, Sashida, Goro, Yue Zhang, Yan Liu, Lee, Jennifer, Menendez, Silvia, Youyang Yang, Xiaomei Yan, Pu Zhang, Tenen, Daniel G., Osato, Motomi, Hsieh, James J.-D., and Nimer, Stephen D.
- Subjects
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LEUKEMIA , *METHYLTRANSFERASES , *TRANSCRIPTION factors , *HISTONES , *GENETIC mutation - Abstract
The mixed-lineage leukemia (MLL) H3K4 methyltransferase protein, and the heterodimeric RUNX1/CBFβ transcription factor complex, are critical for definitive and adult hematopoiesis, and both are frequently targeted in human acute leukemia. We identified a physical and functional interaction between RUNX1 (AML1) and MLL and show that both are required to maintain the histone lysine 4 trimethyl mark (H3K4me3) at 2 critical regulatory regions of the AML1 target gene PU.1. Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation. Furthermore, a subset of previously uncharacterized frame-shift and missense mutations at the N terminus of AML1, found in MDS and AML patients, impairs its interaction with MLL, resulting in loss of the H3K4me3 mark within PU.1 regulatory regions, and decreased PU.1 expression. The interaction between MLL and AML1 provides a mechanism for the sequence-specific binding of MLL to DNA, and identifies RUNX1 target genes as potential effectors of MLL function. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
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