The Med1 Subunit of the Mediator Complex Induces Liver Cell Proliferation and Is Phosphorylated by AMP Kinase

Viswakarma, Navin; Jia, Yuzhi; Bai, Liang; Gao, Qian; Lin, Bingliang; Zhang, Xiaohong; Misra, Parimal; Rana, Ajay; Jain, Sanjay; Gonzalez, Frank J.; Zhu, Yi; Thimmapaya, Bayar; Reddy, Janardan K.

doi:10.1074/jbc.m113.486696

Cited by 19 publications

(23 citation statements)

References 68 publications

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“…The induction of CYP2C9 mRNA levels is mirrored in chromatin accessibility at the HNF4␣ binding region, but CAR and HNF4␣ overexpression combined with silencing MED25 expression results in chromatin condensation and a reduction in CYP2C9 mRNA expression. A similar FAIRE enrichment has been observed in pancreatic islet cell promoters bound by pol II and HNF4␣ (54), and overexpression of Med1 in mouse hepatocytes results in a rapid cellular proliferation response, linking Mediator subunit activity to a concerted physiological response (55). Interestingly, a similar use of DNase hypersensitivity in mouse liver reveals enrichment in hypersensitive sites of H3K27ac markers that positively correlate with sex-biased binding of transcription factors but correlate inversely with H3K27me3 (56).…”

Section: Discussionmentioning

confidence: 56%

Epigenetic Modification of Histone 3 Lysine 27

Englert

Luo

Goldstein

et al. 2015

Journal of Biological Chemistry

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Background: Mediator subunit MED25 associates with hepatocyte nuclear factor 4␣ to initiate activation of select genes. Results: CYP2C9 activation by MED25 involves preinitiation complex formation, H3K27 acetylation, and chromatin conformation changes, and the absence of MED25 results in H3K27 trimethylation and Polycomb group recruitment. Conclusion: MED25 is a key regulator of epigenetic mechanisms. Significance: MED25 regulates human drug metabolism gene CYP2C9 by epigenetic modification.

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Section: Discussionmentioning

confidence: 56%

Epigenetic Modification of Histone 3 Lysine 27

Englert

Luo

Goldstein

et al. 2015

Journal of Biological Chemistry

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“…Since Med1 null hepatocytes failed to respond to PPARα and CAR activators, and Med1 null hepatocytes did not give rise to tumors, it was hypothesized that Med1 is essential for nuclear receptor signal transduction in liver or that this coactivator per se might be a hepatomitogen. Liver cell proliferative response, if any, that is directly related to Med1 expression was assessed by using adenovirally driven expression of Med1 in mouse liver (20). Overexpression of Med1 in liver cells led to the induction of a broad spectrum of genes as well as hepatocyte proliferation (20).…”

Section: Med1 As Key Subunit Of the Mediator Complexmentioning

confidence: 99%

“…Liver cell proliferative response, if any, that is directly related to Med1 expression was assessed by using adenovirally driven expression of Med1 in mouse liver (20). Overexpression of Med1 in liver cells led to the induction of a broad spectrum of genes as well as hepatocyte proliferation (20). Microarray analysis revealed that Med1 upregulates many genes, including those belonging to initiation and elongation of DNA replication and cell cycle progression, those related to cell growth and mitosis (20).…”

Section: Med1 As Key Subunit Of the Mediator Complexmentioning

confidence: 99%

“…Recent evidence indicates a role for Med1, an important subunit of the Mediator complex in controlling the metabolic status and regeneration in liver (19,20). We focus this minireview on Med1 because it is an essential subunit of the multisubunit Mediator complex in regulating fatty acid oxidation and glucose metabolism (19).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, Med1 is also necessary for liver regeneration induced, in particular, by nuclear receptor PPARα and CAR activators (9,21). Recent evidence indicates that Med1 is also sufficient by itself in inducing hepatocellular proliferation (20). …”

Section: Introductionmentioning

confidence: 99%

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Med1 Subunit of the Mediator Complex in Nuclear Receptor-Regulated Energy Metabolism, Liver Regeneration, and Hepatocarcinogenesis

Jia

Viswakarma²,

Reddy³

2014

gene expr

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Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARα-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARα activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARα, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARα, PPARγ, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARα activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic diseases associated with increased energy combustion in liver.

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Overexpression of circFNDC3B promotes the progression of oral tongue squamous cell carcinoma through the miR‐1322/MED1 axis

et al. 2022

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Background The potential role of circFNDC3B in regulating oral tongue squamous cell carcinoma development (OTSCC) remains unknown. Methods The level of circFNDC3B in OTSCC tissues or cell lines was measured and its function in vitro and in vivo was analyzed. Interactions among circFNDC3B, miR‐1322, and MED1 were verified by luciferase reporter and RNA pull‐down assays. Results The level of circFNDC3B in tissues or cell lines of OTSCC was higher than that in control groups. siRNA‐mediated circFNDC3B inhibition resulted in weakened proliferation, migration, and invasion, which was reversed by miR‐1322. Overexpression of MED1 in OTSCC cells partially reversed the tumor suppression functions of si‐circFNDC3B or miR‐1322 mimics in vitro. circFNDC3B overexpression dramatically promoted tumor growth in vivo. circFNDC3B directly bound with miR‐1322 and consequently promoted the MED1 expression in OTSCC cells. Conclusions The circFNDC3B/miR‐1322/MED1 axis participates in OTSCC progression, which may provide novel therapeutic targets for OTSCC.

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The Med1 Subunit of the Mediator Complex Induces Liver Cell Proliferation and Is Phosphorylated by AMP Kinase

Cited by 19 publications

References 68 publications

Epigenetic Modification of Histone 3 Lysine 27

Epigenetic Modification of Histone 3 Lysine 27

Med1 Subunit of the Mediator Complex in Nuclear Receptor-Regulated Energy Metabolism, Liver Regeneration, and Hepatocarcinogenesis

Overexpression of circFNDC3B promotes the progression of oral tongue squamous cell carcinoma through the miR‐1322/MED1 axis

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