The Med1 Subunit of Transcriptional Mediator Plays a Central Role in Regulating CCAAT/Enhancer-binding Protein-β-driven Transcription in Response to Interferon-γ

Li, Hui; Gade, Padmaja; Nallar, Shreeram C.; Raha, Abhijit; Roy, Sitikantha; Karra, Sreenivasu; Reddy, Janardan K.; Reddy, Sekhar P.; Kalvakolanu, Dhananjaya V.

doi:10.1074/jbc.m800604200

Cited by 38 publications

(39 citation statements)

References 59 publications

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“…The transcription factor C/EBPb represses the transcription of some genes by recruiting the Mediator complex with the kinase module to promoters (53). According to this model, C/EBPb phosphorylation might function as a switch that triggers the release of the CDK8 module from the Mediator complex and later induces transcriptional activation.…”

Section: Discussionmentioning

confidence: 99%

The Response of Secondary Genes to Lipopolysaccharides in Macrophages Depends on Histone Deacetylase and Phosphorylation of C/EBPβ

Serrat

Sebastián

Pereira-Lopes

et al. 2014

The Journal of Immunology

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LPS induces the expression of NO synthase 2 (nos2) in macrophages. The expression of this molecule is one of the hallmarks of classical activation. In this paper, we describe that trichostatin A (TSA), which inhibits deacetylase activity, blocks LPS-dependent nos2 expression. TSA specifically inhibits LPS-dependent genes of secondary response, which require new protein synthesis for their induction but not those belonging to the primary response, which do not depend on this process. Deacetylase activity acts at the transcriptional level because RNA polymerase II was not bound after LPS stimulus when we added TSA. A link between the global acetylation caused by HDAC inhibitor and gene promoter recruitment of CDK8 was found. This Mediator complex subunit associates with Med 12, Med13, and cyclin C to form a submodule that is a transcriptional negative regulator. We also found that TSA reduces C/EBPβ phosphorylation without affecting its binding to DNA. Taken together, these results shed light on the molecular mechanisms involved in the transcriptional regulation of LPS-treated macrophages and on how TSA targets critical LPS-induced genes, such as nos2 and tnf-α, in inflammatory macrophage response.

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Section: Discussionmentioning

confidence: 99%

The Response of Secondary Genes to Lipopolysaccharides in Macrophages Depends on Histone Deacetylase and Phosphorylation of C/EBPβ

Serrat

Sebastián

Pereira-Lopes

et al. 2014

The Journal of Immunology

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“…Since the N terminus of MED1 rescues the growth of MED1-deficient primary mammary epithelial cells immortalized by Notch4 (44), the N terminus of MED1 might be the cardinal component of MED1-mediated cell growth. Candidate activators include BRCA1 (39) and C/ERP␤ (23). In this regard, it is notable that N-terminal MED1(1-602) and MED1(603-703) domains might have cooperative roles in mitogenicity (this study).…”

Section: Med24mentioning

confidence: 99%

Mediator Subunits MED1 and MED24 Cooperatively Contribute to Pubertal Mammary Gland Development and Growth of Breast Carcinoma Cells

Hasegawa¹,

Sumitomo²,

Fujita³

et al. 2012

Molecular and Cellular Biology

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The Mediator subunit MED1 is essential for mammary gland development and lactation, whose contribution through direct interaction with estrogen receptors (ERs) is restricted to involvement in pubertal mammary gland development and luminal cell differentiation. Here, we provide evidence that the MED24-containing submodule of Mediator functionally communicates specifically with MED1 in pubertal mammary gland development. Mammary glands from MED1/MED24 double heterozygous knockout mice showed profound retardation in ductal branching during puberty, while single haploinsufficient glands developed normally. DNA synthesis of both luminal and basal cells were impaired in double mutant mice, and the expression of ERtargeted genes encoding E2F1 and cyclin D1, which promote progression through the G 1 /S phase of the cell cycle, was attenuated. Luciferase reporter assays employing double mutant mouse embryonic fibroblasts showed selective impairment in ER functions. Various breast carcinoma cell lines expressed abundant amounts of MED1, MED24, and MED30, and attenuated expression of MED1 and MED24 in breast carcinoma cells led to attenuated DNA synthesis and growth. These results indicate functional communications between the MED1 subunit and the MED24-containing submodule that mediate estrogen receptor functions and growth of both normal mammary epithelial cells and breast carcinoma cells. N uclear receptors, which include steroid and nonsteroid hormone receptors, comprise a superfamily of DNA-bound transcriptional regulators that are activated in response to specific small lipophilic ligands and that play major physiological roles in cell growth, differentiation, and homeostasis (reviewed in references 10 and 25). Estrogen receptor ␣ (ER␣) is the key activator that leads to growth of the mammary glands during adolescence, as well as during pregnancy, in response to elevated plasma estrogen levels. Among the hormone-responsive genes transcribed under the control of ER␣ is another steroid hormone receptor, progesterone receptor (PR), which in concert with ER␣, plays an important role in mammary gland development (5).The metazoan Mediator/TRAP coactivator complex is a master transcriptional coregulator composed of about 30 subunits and is structurally subdivided into head, body, and tail modules. It constitutes a subcomplex of the RNA polymerase II holoenzyme and integrates a wide variety of intracellular signals through specific interactions of activators with specific Mediator subunits that reside predominantly at its tail module (reviewed in references 4, 6, 15, 20, and 24). We have proposed a multistep model for nuclear receptor-induced transcriptional activation (15). In this model, histone-modifying coactivators that possess either histone acetyltransferase or histone methyltransferase activities first interact with ligand-bound nuclear receptors, and chromatin structure is subsequently relaxed. Then an exchange of coactivators takes place and the Mediator is bound to nuclear receptors through two canonical LxxLL nuc...

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“…Of particular interest, the MED1 subunit of Mediator regulates the function of important transcription factors in adipocytes, including PPARg, PPARGC1a, C/EBPb, and the thyroid receptor (TR) (Yuan et al 1998;Wallberg et al 2003;Li et al 2008;Borggrefe and Yue 2011), which themselves also cooperate with PRDM16. Med1 is expressed at slightly higher levels in BAT relative to epididymal or inguinal WAT, and its expression levels increase during the process of adipogenesis in brown fat cells (Supplemental Fig.…”

Section: Prdm16 Binding Is Enriched At Bat-selective Genesmentioning

confidence: 99%

PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program

Harms¹,

et al. 2015

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PR (PRD1-BF1-RIZ1 homologous) domain-containing 16 (PRDM16) drives a brown fat differentiation program, but the mechanisms by which PRDM16 activates brown fat-selective genes have been unclear. Through chromatin immunoprecipitation (ChIP) followed by deep sequencing (ChIP-seq) analyses in brown adipose tissue (BAT), we reveal that PRDM16 binding is highly enriched at a broad set of brown fat-selective genes. Importantly, we found that PRDM16 physically binds to MED1, a component of the Mediator complex, and recruits it to superenhancers at brown fat-selective genes. PRDM16 deficiency in BAT reduces MED1 binding at PRDM16 target sites and causes a fundamental change in chromatin architecture at key brown fat-selective genes. Together, these data indicate that PRDM16 controls chromatin architecture and superenhancer activity in BAT.

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The Med1 Subunit of Transcriptional Mediator Plays a Central Role in Regulating CCAAT/Enhancer-binding Protein-β-driven Transcription in Response to Interferon-γ

Cited by 38 publications

References 59 publications

The Response of Secondary Genes to Lipopolysaccharides in Macrophages Depends on Histone Deacetylase and Phosphorylation of C/EBPβ

The Response of Secondary Genes to Lipopolysaccharides in Macrophages Depends on Histone Deacetylase and Phosphorylation of C/EBPβ

Mediator Subunits MED1 and MED24 Cooperatively Contribute to Pubertal Mammary Gland Development and Growth of Breast Carcinoma Cells

PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program

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