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The mediator complex subunit 23 (MED23) gene encodes a protein that acts as a tail module mediator complex, a multi-subunit co-activator involved in several cellular activities. MED23 has been shown to have substantial roles in myogenesis and other molecular mechanisms. The functions of MED23 in the neurological system remain unclear and the clinical phenotype is not thoroughly described. Whole exome sequencing was used to identify a novel mutation in the MED23 gene. DNA capture probes using next-generation sequencing-based copy number variation analysis with Illumina array were performed. The clinical, demographic, neuroimaging, and electrophysiological data of the patients were collected, and similarly, the data of all reported cases in the literature were extracted to compare findings. Screening a total of 9,662 articles, we identified 22 main regulatory processes for the MED23 gene, including suppressive activity for carcinogenic processes. MED23 is also involved in the brain’s neurogenesis and functions. The identified cases mainly presented with intellectual disability (87.5%) and developmental delay (50%). Seizures were present in only 18.75% of the patients. Slow backgrounds and spike and sharp-wave complexes were reported on the electroencephalogram (EEG) of a few patients and delayed myelination, thin corpus callosum, and pontine hypoplasia on magnetic resonance imaging (MRI). The MED23 gene regulates several processes in which its understanding promotes considerable therapeutic potential for patients. It is crucial to consider genetic and laboratory testing, particularly when encountering potential carriers. Intellectual disability and developmental delay are the most notable clinical signs with heterogeneous features on EEG and MRI. [ABSTRACT FROM AUTHOR]

The maintenance of nuclear shape is essential for cellular homeostasis and disruptions in this process have been linked to various pathological conditions, including cancer, laminopathies, and aging. Despite the significance of nuclear shape, the precise molecular mechanisms controlling it are not fully understood. In this study, we have identified the YEATS domain-containing protein 4 (GAS41) as a previously unidentified factor involved in regulating nuclear morphology. Genetic ablation of GAS41 in colorectal cancer cells resulted in significant abnormalities in nuclear shape and inhibited cancer cell proliferation both in vitro and in vivo. Restoration experiments revealed that wild-type GAS41, but not a YEATS domain mutant devoid of histone H3 lysine 27 acetylation or crotonylation (H3K27ac/cr) binding, rescued the aberrant nuclear phenotypes in GAS41-deficient cells, highlighting the importance of GAS41’s binding to H3K27ac/cr in nuclear shape regulation. Further experiments showed that GAS41 interacts with H3K27ac/cr to regulate the expression of key nuclear shape regulators, including LMNB1, LMNB2, SYNE4, and LEMD2. Mechanistically, GAS41 recruited BRD2 and the Mediator complex to gene loci of these regulators, promoting their transcriptional activation. Disruption of GAS41-H3K27ac/cr binding caused BRD2, MED14 and MED23 to dissociate from gene loci, leading to nuclear shape abnormalities. Overall, our findings demonstrate that GAS41 collaborates with BRD2 and the Mediator complex to control the expression of crucial nuclear shape regulators.

Biallelic loss-of-function variants in MED23 cause a recessive syndromic intellectual disability condition with or without epilepsy (MRT18). Due to the small number of reported individuals, the clinical phenotype of the disorder has not been fully delineated yet, and the spectrum and frequency of neurologic features have not been fully characterized. Here, we report a 5-year-old girl with compound heterozygous for two additional MED23 variants. Besides global developmental delay, axial hypotonia and peripheral increased muscular tone, absent speech, and generalized tonic seizures, which fit well MRT18, the occurrence of postnatal progressive microcephaly has been here documented. A retrospective assessment of the previously reported clinical data for these subjects confirms the occurrence of postnatal progressive microcephaly as a previously unappreciated feature of the phenotype of MED23-related disorder. [ABSTRACT FROM AUTHOR]

Biallelic loss-of-function variants in MED23 cause a recessive syndromic intellectual disability condition with or without epilepsy (MRT18). Due to the small number of reported individuals, the clinical phenotype of the disorder has not been fully delineated yet, and the spectrum and frequency of neurologic features have not been fully characterized. Here, we report a 5-year-old girl with compound heterozygous for two additional MED23 variants. Besides global developmental delay, axial hypotonia and peripheral increased muscular tone, absent speech, and generalized tonic seizures, which fit well MRT18, the occurrence of postnatal progressive microcephaly has been here documented. A retrospective assessment of the previously reported clinical data for these subjects confirms the occurrence of postnatal progressive microcephaly as a previously unappreciated feature of the phenotype of MED23-related disorder.

The maintenance of nuclear shape is essential for cellular homeostasis and disruptions in this process have been linked to various pathological conditions, including cancer, laminopathies, and aging. Despite the significance of nuclear shape, the precise molecular mechanisms controlling it are not fully understood. In this study, we have identified the YEATS domain-containing protein 4 (GAS41) as a previously unidentified factor involved in regulating nuclear morphology. Genetic ablation of GAS41 in colorectal cancer cells resulted in significant abnormalities in nuclear shape and inhibited cancer cell proliferation both in vitro and in vivo. Restoration experiments revealed that wild-type GAS41, but not a YEATS domain mutant devoid of histone H3 lysine 27 acetylation or crotonylation (H3K27ac/cr) binding, rescued the aberrant nuclear phenotypes in GAS41-deficient cells, highlighting the importance of GAS41's binding to H3K27ac/cr in nuclear shape regulation. Further experiments showed that GAS41 interacts with H3K27ac/cr to regulate the expression of key nuclear shape regulators, including LMNB1, LMNB2, SYNE4, and LEMD2. Mechanistically, GAS41 recruited BRD2 and the Mediator complex to gene loci of these regulators, promoting their transcriptional activation. Disruption of GAS41-H3K27ac/cr binding caused BRD2, MED14 and MED23 to dissociate from gene loci, leading to nuclear shape abnormalities. Overall, our findings demonstrate that GAS41 collaborates with BRD2 and the Mediator complex to control the expression of crucial nuclear shape regulators. [Display omitted] [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death worldwide. 85 % of lung cancers are categorized by their histological types as a non-small cell lung cancer (NSCLC) subtype. While the MED23 subunit of the mediator complex has been implicated in lung cancer development, the precise underlying mechanism remains unclear. Our research indicates that elevated MED23 expression is linked to reduced overall survival rates in NSCLC. Depletion of MED23 triggers premature senescence in NSCLC cells. Furthermore, through co-IP and mass spectrometry analyses, we have identified BCLAF1 as a binding partner of MED23, with subsequent confirmation via PLA assays. Subsequently, NUPR1, a transcriptional cofactor known to induce premature senescence in lung cancer cells by disrupting autophagic processes, was validated as a downstream target of the MED23/BCLAF1 complex through RNA-seq and ChIP assays. Thus, the interaction between MED23 and BCLAF1 regulates NUPR1 expression, impacting autophagic flux and leading to premature senescence in NSCLC cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Muscle stem cells (MuSCs) contribute to a robust muscle regeneration process after injury, which is highly orchestrated by the sequential expression of multiple key transcription factors. However, it remains unclear how key transcription factors and cofactors such as the Mediator complex cooperate to regulate myogenesis. Here, we show that the Mediator Med23 is critically important for MuSC-mediated muscle regeneration. Med23 is increasingly expressed in activated/proliferating MuSCs on isolated myofibers or in response to muscle injury. Med23 deficiency reduced MuSC proliferation and enhanced its precocious differentiation, ultimately compromising muscle regeneration. Integrative analysis revealed that Med23 oppositely impacts Ternary complex factor (TCF)-targeted MuSC proliferation genes and myocardin-related transcription factor (MRTF)-targeted myogenic differentiation genes. Consistently, Med23 deficiency decreases the ETS-like transcription factor 1 (Elk1)/serum response factor (SRF) binding at proliferation gene promoters but promotes MRTF-A/SRF binding at myogenic gene promoters. Overall, our study reveals the important transcriptional control mechanism of Med23 in balancing MuSC proliferation and differentiation in muscle regeneration. [Display omitted] • Mediator Med23 is increasingly expressed in MuSCs in response to muscle injury • Med23 deficiency in MuSCs decreases proliferation and promotes precocious differentiation • Med23 oppositely regulates TCF-targeted genes and MRTF-targeted genes • Med23 deficiency reduces Elk1/SRF binding but favors MRTF-A/SRF binding to respective genes Fang et al. demonstrate that Mediator Med23 in myoblasts oppositely affects the binding of Elk1/SRF and MRTF-A/SRF to control the respective gene expression, which provides mechanistic insights into a transcriptional switch from proliferation to differentiation during muscle regeneration. [ABSTRACT FROM AUTHOR]

Development of the vertebrate head is a complex and dynamic process, which requires integration of all three germ layers and their derivatives. Of special importance are ectoderm-derived cells that form the cranial placodes, which then differentiate into the cranial ganglia and sensory organs. Critical to a fully functioning head, defects in cranial placode and sensory organ development can result in congenital craniofacial anomalies. In a forward genetic screen aimed at identifying novel regulators of craniofacial development, we discovered an embryonically lethal mouse mutant, snouty, which exhibits malformation of the facial prominences, cranial nerves and vasculature. The snouty mutation was mapped to a single nucleotide change in a ubiquitously expressed gene, Med23, which encodes a subunit of the global transcription co-factor complex, Mediator. Phenotypic analyses revealed that the craniofacial anomalies, particularly of the cranial ganglia, were caused by a failure in the proper specification of cranial placode neuronal precursors. Molecular analyses determined that defects in cranial placode neuronal differentiation in Med23sn/sn mutants were associated with elevated WNT/β-catenin signaling, which can be partially rescued through combined Lrp6 and Wise loss-of-function. Our work therefore reveals a surprisingly tissue specific role for the ubiquitously expressed mediator complex protein Med23 in placode differentiation during cranial ganglia development. This highlights the importance of coupling general transcription to the regulation of WNT signaling during embryogenesis.

Development of the vertebrate head is a complex and dynamic process, which requires integration of all three germ layers and their derivatives. Of special importance are ectoderm-derived cells that form the cranial placodes, which then differentiate into the cranial ganglia and sensory organs. Critical to a fully functioning head, defects in cranial placode and sensory organ development can result in congenital craniofacial anomalies. In a forward genetic screen aimed at identifying novel regulators of craniofacial development, we discovered an embryonically lethal mouse mutant, snouty , which exhibits malformation of the facial prominences, cranial nerves and vasculature. The snouty mutation was mapped to a single nucleotide change in a ubiquitously expressed gene, Med23 , which encodes a subunit of the global transcription co-factor complex, Mediator. Phenotypic analyses revealed that the craniofacial anomalies, particularly of the cranial ganglia, were caused by a failure in the proper specification of cranial placode neuronal precursors. Molecular analyses determined that defects in cranial placode neuronal differentiation in Med23 sn/sn mutants were associated with elevated WNT/β-catenin signaling, which can be partially rescued through combined Lrp6 and Wise loss-of-function. Our work therefore reveals a surprisingly tissue specific role for the ubiquitously expressed mediator complex protein Med23 in placode differentiation during cranial ganglia development. This highlights the importance of coupling general transcription to the regulation of WNT signaling during embryogenesis. [ABSTRACT FROM AUTHOR]

DNA repair is related to many physiological and pathological processes, including pigmentation. Little is known about the role of the transcriptional cofactor Mediator complex in DNA repair and pigmentation. Here, we demonstrate that Mediator MED23 plays an important role in coupling UV-induced DNA repair to pigmentation. The loss of Med23 specifically impairs the pigmentation process in melanocyte-lineage cells and in zebrafish. Med23 deficiency leads to enhanced nucleotide excision repair (NER) and less DNA damage following UV radiation because of the enhanced expression and recruitment of NER factors to chromatin for genomic stability. Integrative analyses of melanoma cells reveal that MED23 controls the expression of a melanocyte master regulator, Mitf, by modulating its distal enhancer activity, leading to opposing effects on pigmentation and DNA repair. Collectively, the Mediator MED23/MITF axis connects DNA repair to pigmentation, thus providing molecular insights into the DNA damage response and skin-related diseases.

Six initially equivalent, multipotential Vulval Precursor Cells (VPCs) in Caenorhabditis elegans adopt distinct cell fates in a precise spatial pattern, with each fate associated with transcription of different target genes. The pattern is centered on a cell that adopts the "1°" fate through Epidermal Growth Factor Receptor (EGFR) activity, and produces a lateral signal composed of ligands that activate LIN-12/Notch in the two flanking VPCs to cause them to adopt "2°" fate. Here, we investigate orthologs of a transcription complex that acts in mammalian EGFR signaling--lin-1/Elk1, sur-2/Med23, and the Cdk8 Kinase module (CKM)--previously implicated in aspects of 1° fate in C. elegans and show they act in different combinations for different processes for 2° fate. When EGFR is inactive, the CKM, but not SUR-2, helps to set a threshold for LIN-12/Notch activity in all VPCs. When EGFR is active, all three factors act to resist LIN-12/Notch, as revealed by the reduced ability of ectopically-activated LIN-12/Notch to activate target gene reporters. We show that overcoming this resistance in the 1° VPC leads to repression of lateral signal gene reporters, suggesting that resistance to LIN-12/Notch helps ensure that P6.p becomes a robust source of the lateral signal. In addition, we show that sur-2/Med23 and lin-1/Elk1, and not the CKM, are required to promote endocytic downregulation of LIN-12-GFP in the 1° VPC. Finally, our analysis using cell fate reporters reveals that both EGFR and LIN-12/Notch signal transduction pathways are active in all VPCs in lin-1/Elk1 mutants, and that lin-1/Elk1 is important for integrating EGFR and lin-12/Notch signaling inputs in the VPCs so that the proper gene complement is transcribed. [ABSTRACT FROM AUTHOR]

Summary DNA repair is related to many physiological and pathological processes, including pigmentation. Little is known about the role of the transcriptional cofactor Mediator complex in DNA repair and pigmentation. Here, we demonstrate that Mediator MED23 plays an important role in coupling UV-induced DNA repair to pigmentation. The loss of Med23 specifically impairs the pigmentation process in melanocyte-lineage cells and in zebrafish. Med23 deficiency leads to enhanced nucleotide excision repair (NER) and less DNA damage following UV radiation because of the enhanced expression and recruitment of NER factors to chromatin for genomic stability. Integrative analyses of melanoma cells reveal that MED23 controls the expression of a melanocyte master regulator, Mitf , by modulating its distal enhancer activity, leading to opposing effects on pigmentation and DNA repair. Collectively, the Mediator MED23/MITF axis connects DNA repair to pigmentation, thus providing molecular insights into the DNA damage response and skin-related diseases. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 1 (HSV-1) has long been suspected to play a role in Alzheimer's disease (AD), the most common form of dementia. IFN-lambda (IFN-λ) is one of the key cytokine in innate antiviral defenses and, in particular, has an appreciable antiviral activity against HSV-1 infection. IFN-λ expression is regulated by the interaction between two different proteins: Mediator Complex 23 (MED23) and Interferon-Responsive Transcription Factor 7 (IRF7); single nucleotide polymorphisms (SNPs) in these genes as well as in IFNL3 were shown to be differently distributed in AD patients. In this study, allelic discrimination analysis for IFNL3 rs12979860, MED23 rs3756784, and IRF7 rs6598008, as well as IFN-λ serum concentration and anti-HSV-1 antibody (Ab) titers were performed in 79 AD patients, 57 mild cognitive impairment (MCI) individuals, and 81 healthy controls (HC) who were HSV-1-seropositive. Results showed that INF-λ serum concentration was increased in AD and MCI carrying the IFNL3 T allele compared to HC (AD versus HC: p = 0.014; MCI versus HC: p = 0.029), with the highest anti-HSV-1 Ab titers seen in AD patients carrying the IFNL3 CC genotype (p = 0.012 versus HC). Notably, anti-HSV-1 Ab titers were higher in AD and MCI individuals carrying the IRF7 AA genotype compared to HC (p = 0.018 for both). MED23 polymorphisms did not show any statistical association either with serum IFN-λ or with anti-HSV-1 Ab. Data herein suggest that the IFNL3 rs12979860 and IRF7 rs6598008 polymorphisms modulate immune responses against HSV-1 via their effect on the IFN-λ pathway. These results help to clarify the possible role of HSV-1 infection in AD pathogenesis. [ABSTRACT FROM AUTHOR]

We investigated the role of the transcriptional mediator subunit 23 (MED23) in everolimus drug resistance, invasion and metastasis during breast cancer treatment and its molecular mechanism. We also evaluated the endocrinotherapy and prevention method for breast cancer. Breast cancer cell strains were established that can continuously express MED23, as well as inducible MED23-shRNA expression plasmids. The inductive agent, doxycycline (Dox), was added to the water for long-term silencing of MED23 in intratumoral cells. We conducted experiments on the role of MED23 in the regulation of invasion and metastasis of breast cancer using cell culture, western blotting, MTT proliferation experiment, fluorescent quantitative PCR and chromatin immunoprecipitation (ChIP). The silencing of MED23 significantly inhibited cellular growth and proliferation as well as soft agar cloning. Silencing of MED23 strengthened the sensitivity of the everolimus-resistant breast cancer cell strains BT474 and MCF-7/ADM cells to everolimus medication. The silencing of MED23, in combination with everolimus, inhibits the cell cycle progress of breast cancer cells. ChIP indicated that the mutual regulation of HER2 and MED23 also participates in the formation of the everolimus drug resistance mechanism. Therefore, MED23 plays an important role in everolimus drug resistance, invasion, and metastasis of breast cancer. As a potential molecular therapeutic target of breast cancer, MED23 overcomes drug resistance in clinical endocrinotherapy and controls the distal relapse and metastasis in breast cancer by the targeted silencing of MED23. [ABSTRACT FROM AUTHOR]

We report a new patient with refractory epilepsy associated with a novel pathogenic homozygous MED23 variant. This 7.5-year-old boy from consanguineous parents had infantile onset global developmental delay and refractory epilepsy. He was treated with the ketogenic diet at 2.5 years of age and became seizure free on the first day. He had microcephaly and truncal hypotonia. His brain MRI showed delayed myelination and thin corpus callosum. He was enrolled in a whole exome sequencing research study, which identified a novel, homozygous, likely pathogenic (c.1937A>G; p.Gln646Arg) variant in MED23. MED23 is a regulator of energy homeostasis and glucose production. Liver-specific Med23-knockout mice showed reduced liver gluconeogenesis and lower blood glucose levels compared to control mice. This is the first patient with documented refractory epilepsy caused by a novel homozygous pathogenic variant in MED23 expanding the phenotypic spectrum. Identification of the underlying genetic defect in MED23 sheds light on the possible mechanism of complete response to the ketogenic diet in this child. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Cell signaling pathways that control proliferation and determine cell fates are tightly regulated to prevent developmental anomalies and cancer. Transcription factors and coregulators are important effectors of signaling pathway output, as they regulate downstream gene programs. In Caenorhabditis elegans, several subunits of the Mediator transcriptional coregulator complex promote or inhibit vulva development, but pertinent mechanisms are poorly defined. Here, we show that Mediator's dissociable cyclin dependent kinase 8 (CDK8) module (CKM), consisting of cdk-8, cic-1/Cyclin C, mdt-12/dpy-22, and mdt-13/let-19, is required to inhibit ectopic vulval cell fates downstream of the epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK) pathway. cdk-8 inhibits ectopic vulva formation by acting downstream of mpk-1/ERK, cell autonomously in vulval cells, and in a kinasedependent manner. We also provide evidence that the CKM acts as a corepressor for the Ets-family transcription factor LIN-1, as cdk-8 promotes transcriptional repression by LIN-1. In addition, we find that CKM mutation alters Mediator subunit requirements in vulva development: the mdt-23/sur-2 subunit, which is required for vulva development in wild-type worms, is dispensable for ectopic vulva formation in CKM mutants, which instead display hallmarks of unrestrained Mediator tail module activity. We propose a model whereby the CKM controls EGFR-Ras-ERK transcriptional output by corepressing LIN-1 and by fine tuning Mediator specificity, thus balancing transcriptional repression vs. activation in a critical developmental signaling pathway. Collectively, these data offer an explanation for CKM repression of EGFR signaling output and ectopic vulva formation and provide the first evidence of Mediator CKM-tail module subunit crosstalk in animals. [ABSTRACT FROM AUTHOR]

Background and Aim Hepatocellular carcinoma ( HCC) is the fifth most frequent cancer in the world. However, the molecular mechanisms involved in HCC are still poorly understood. Here, we study the role of mediator subunit 23 ( MED23), a component of the Mediator complex, in hepatocarcinogenesis. Methods We detected MED23 expression in HCC samples by real-time polymerase chain reaction ( PCR) and immunohistochemistry analysis. We also knocked down and overexpressed MED23 to explore its functional role in hepatoma cell growth. The cell cycle was examined by flow cytometry analysis, and protein expression was examined by Western blot. A xenograft mouse model was used to determine whether MED23 is involved in tumorigenesis. Results MED23 was frequently upregulated in human HCC tissues compared with paired adjacent non-tumorous liver tissues. The hepatoma cells also showed increased MED23 expression. MED23 knockdown inhibited hepatoma cell growth, whereas overexpression of MED23 promoted cell growth. Knockdown of MED23 induced a G1 to S phase arrest. Moreover, MED23 regulated the expression of p16 INK4a (p16) and the phosphorylation of retinoblastoma protein ( Rb). p16 was transcriptionally upregulated, and its promoter was demethylated. The G1 to S phase arrest induced by MED23 knockdown was aborted after p16 was silenced. Furthermore, MED23 knockdown suppressed tumorigenesis and regulated p16/ Rb signaling in vivo. Conclusions Taken together, our study suggests that MED23 plays an important role in hepatocarcinogenesis, and it may be a novel target for HCC therapy. [ABSTRACT FROM AUTHOR]

Intellectual disability (ID) is a heterogeneous condition arising from a variety of environmental and genetic factors. Among these causes are defects in transcriptional regulators. Herein, we report on two brothers in a nonconsanguineous family with novel compound heterozygous, disease-segregating mutations (NM_015979.3: [3656A > G];[4006C > T], NP_057063.2: [H1219R];[R1336X]) in MED23. This gene encodes a subunit of the Mediator complex that modulates the expression of RNA polymerase II-dependent genes. These brothers, who had profound ID, spasticity, congenital heart disease, brain abnormalities, and atypical electroencephalography, represent the first case of MED23-associated ID in a non-consanguineous family. They also expand upon the clinical features previously reported for mutations in this gene. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Unraveling the mechanisms underlying early neural differentiation of embryonic stem cells (ESCs) is crucial to developing cell-based therapies of neurodegenerative diseases. Neural fate acquisition is proposed to be controlled by a 'default' mechanism, for which the molecular regulation is not well understood. In this study, we investigated the functional roles of Mediator Med23 in pluripotency and lineage commitment of murine ESCs. Unexpectedly, we found that, despite the largely unchanged pluripotency and self-renewal of ESCs, Med23 depletion rendered the cells prone to neural differentiation in different differentiation assays. Knockdown of two other Mediator subunits, Med1 and Med15, did not alter the neural differentiation of ESCs. Med15 knockdown selectively inhibited endoderm differentiation, suggesting the specificity of cell fate control by distinctive Mediator subunits. Gene profiling revealed that Med23 depletion attenuated BMP signaling in ESCs. Mechanistically, MED23 modulated Bmp4 expression by controlling the activity of ETS1, which is involved in Bmp4 promoter-enhancer communication. Interestingly, med23 knockdown in zebrafish embryos also enhanced neural development at early embryogenesis, which could be reversed by co-injection of bmp4 mRNA. Taken together, our study reveals an intrinsic, restrictive role of MED23 in early neural development, thus providing new molecular insights for neural fate determination. [ABSTRACT FROM AUTHOR]

Mediator complex subunit MED23 has been reported to facilitate the transformation induced by oncogenic Ras in non-small-cell lung carcinoma (NSCLC). However, the expression pattern and biological functions of MED23 in the progression of NSCLC are not fully understood. In this study, it was found that the expression of MED23 was significantly upregulated in NSCLC samples compared to their adjacent normal tissues. Moreover, in the biological function studies, overexpression of MED23 was further validated to promote the growth, migration, and metastasis of NSCLC cells, while knockdown of the expression of MED23 inhibited the growth, migration, and metastasis of NSCLC cells in vitro and in vivo. Mechanistically, MED23 was found to interact with beta-catenin and activate beta-catenin/TCF signaling. Our study demonstrated that MED23 played an oncogenic role in the progression of NSCLC and that MED23 might be a promising target for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

We investigated the role of the transcriptional mediator subunit 23 (MED23) in everolimus drug resistance, invasion and metastasis during breast cancer treatment and its molecular mechanism. We also evaluated the endocrinotherapy and prevention method for breast cancer. Breast cancer cell strains were established that can continuously express MED23, as well as inducible MED23-shRNA expression plasmids. The inductive agent, doxycycline (Dox), was added to the water for long-term silencing of MED23 in intratumoral cells. We conducted experiments on the role of MED23 in the regulation of invasion and metastasis of breast cancer using cell culture, western blotting, MTT proliferation experiment, fluorescent quantitative PCR and chromatin immunoprecipitation (ChIP). The silencing of MED23 significantly inhibited cellular growth and proliferation as well as soft agar cloning. Silencing of MED23 strengthened the sensitivity of the everolimus-resistant breast cancer cell strains BT474 and MCF-7/ADM cells to everolimus medication. The silencing of MED23, in combination with everolimus, inhibits the cell cycle progress of breast cancer cells. ChIP indicated that the mutual regulation of HER2 and MED23 also participates in the formation of the everolimus drug resistance mechanism. Therefore, MED23 plays an important role in everolimus drug resistance, invasion, and metastasis of breast cancer. As a potential molecular therapeutic target of breast cancer, MED23 overcomes drug resistance in clinical endocrinotherapy and controls the distal relapse and metastasis in breast cancer by the targeted silencing of MED23.

Herpes simplex virus type 1 (HSV-1) has long been suspected to play a role in Alzheimer's disease (AD), the most common form of dementia. IFN-lambda (IFN-λ) is one of the key cytokine in innate antiviral defenses and, in particular, has an appreciable antiviral activity against HSV-1 infection. IFN-λ expression is regulated by the interaction between two different proteins: Mediator Complex 23 (MED23) and Interferon-Responsive Transcription Factor 7 (IRF7); single nucleotide polymorphisms (SNPs) in these genes as well as in IFNL3 were shown to be differently distributed in AD patients. In this study, allelic discrimination analysis for IFNL3 rs12979860, MED23 rs3756784, and IRF7 rs6598008, as well as IFN-λ serum concentration and anti-HSV-1 antibody (Ab) titers were performed in 79 AD patients, 57 mild cognitive impairment (MCI) individuals, and 81 healthy controls (HC) who were HSV-1-seropositive. Results showed that INF-λ serum concentration was increased in AD and MCI carrying the IFNL3 T allele compared to HC (AD versus HC: p = 0.014; MCI versus HC: p = 0.029), with the highest anti-HSV-1 Ab titers seen in AD patients carrying the IFNL3 CC genotype (p = 0.012 versus HC). Notably, anti-HSV-1 Ab titers were higher in AD and MCI individuals carrying the IRF7 AA genotype compared to HC (p = 0.018 for both). MED23 polymorphisms did not show any statistical association either with serum IFN-λ or with anti-HSV-1 Ab. Data herein suggest that the IFNL3 rs12979860 and IRF7 rs6598008 polymorphisms modulate immune responses against HSV-1 via their effect on the IFN-λ pathway. These results help to clarify the possible role of HSV-1 infection in AD pathogenesis.

Unraveling the mechanisms underlying early neural differentiation of embryonic stem cells (ESCs) is crucial to developing cell-based therapies of neurodegenerative diseases. Neural fate acquisition is proposed to be controlled by a 'default' mechanism, for which the molecular regulation is not well understood. In this study, we investigated the functional roles of Mediator Med23 in pluripotency and lineage commitment of murine ESCs. Unexpectedly, we found that, despite the largely unchanged pluripotency and self-renewal of ESCs, Med23 depletion rendered the cells prone to neural differentiation in different differentiation assays. Knockdown of two other Mediator subunits, Med1 and Med15, did not alter the neural differentiation of ESCs. Med15 knockdown selectively inhibited endoderm differentiation, suggesting the specificity of cell fate control by distinctive Mediator subunits. Gene profiling revealed that Med23 depletion attenuated BMP signaling in ESCs. Mechanistically, MED23 modulated Bmp4 expression by controlling the activity of ETS1, which is involved in Bmp4 promoter-enhancer communication. Interestingly, med23 knockdown in zebrafish embryos also enhanced neural development at early embryogenesis, which could be reversed by co-injection of bmp4 mRNA. Taken together, our study reveals an intrinsic, restrictive role of MED23 in early neural development, thus providing new molecular insights for neural fate determination., (© 2015. Published by The Company of Biologists Ltd.)

The Mediator complex functions as a control center, orchestrating diverse signaling, gene activities, and biological processes. However, how Mediator subunits determine distinct cell fates remains to be fully elucidated. Here, we show that Mediator MED23 controls the cell fate preference that directs differentiation into smooth muscle cells (SMCs) or adipocytes. Med23 deficiency facilitates SMC differentiation but represses adipocyte differentiation from the multipotent mesenchymal stem cells. Gene profiling revealed that the presence or absence of Med23 oppositely regulates two sets of genes: the RhoA/MAL targeted cytoskeleton/SMC genes and the Ras/ELK1 targeted growth/adipogenic genes. Mechanistically, MED23 favors ELK1-SRF binding to SMC gene promoters for repression, whereas the lack of MED23 favors MAL-SRF binding to SMC gene promoters for activation. Remarkably, the effect of MED23 on SMC differentiation can be recapitulated in zebrafish embryogenesis. Collectively, our data demonstrate the dual, opposing roles for MED23 in regulating the cytoskeleton/SMC and growth/adipogenic gene programs, suggesting its "Ying-Yang" function in directing adipogenesis versus SMC differentiation. [ABSTRACT FROM AUTHOR]