Unraveling framework of the ancestral Mediator complex in human diseases

Napoli, Claudio; Sessa, Marcella; Infante, Teresa; Casamassimi, Amelia

doi:10.1016/j.biochi.2011.09.016

Cited by 49 publications

(34 citation statements)

References 121 publications

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“…Whether the lack of a Mediator subunit could minimize or prevent expression of a specific set of genes remains to be established, but a growing number of studies have proposed Mediator as a therapeutic target for several diseases such as cancer, cardiovascular disease, and metabolic and neurological disorders (12,20). Targeting a single Mediator subunit might block a specific pathway but allow a majority of cellular transcription to function normally, and this effect could vary depending both on gene and cell type.…”

Section: Discussionmentioning

confidence: 99%

“…Several other proteins have been previously identified (9) but remain to be confirmed, including those of the Mediator complex (10,11), a large multisubunit complex that regulates RNAP II transcribed genes. In humans, MED is composed of 28 proteins assembled in four distinct modules as follows: the "Head," which contacts the RNAP II; the "Middle" and "Tail" that transfer regulatory signals after interacting with transcription factors to the Head; and the "CDK8 module," including MED12 and MED13 that associate less stably to the whole complex and have activating and repressing functions (12)(13)(14). These different subunits can contact various transcriptional regulators and act together as an adaptor to convey transcription signals from activators to the general transcription machinery, helping the initiation of transcription by RNAP II (15)(16)(17).…”

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confidence: 99%

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Characterization of the Influence of Mediator Complex in HIV-1 Transcription

Ruiz

Pauls

Badía

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Characterization of the Influence of Mediator Complex in HIV-1 Transcription

Ruiz

Pauls

Badía

et al. 2014

Journal of Biological Chemistry

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“…The study of the human genome and its position on the phylogenetic tree of life can help identify genes responsible for higher brain functions. Further, as we learn more about the human genome, we are discovering protooncogenes involved in cancer [5,6]. It is particularly important to focus on understanding the specific genetic mutations and epigenetic influences in different types of cancer because the overall incidence of cancer is increasing rapidly, with a combined annual increase of approximately 3.5% across all cancers [7].…”

Section: Introductionmentioning

confidence: 99%

All-or-(N)One – an epistemological characterization of the human tumorigenic neuronal paralogous FAM72 gene loci

et al. 2015

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FAM72 is a novel neuronal progenitor cell (NPC) self-renewal supporting protein expressed under physiological conditions at low levels in other tissues. Accumulating data indicate the potential pivotal tumourigenic effects of FAM72. Our in silico human genome-wide analysis (GWA) revealed that the FAM72 gene family consists of four human-specific paralogous members, all of which are located on chromosome (chr) 1. Unique asymmetric FAM72 segmental gene duplications are most likely to have occurred in conjunction with the paired genomic neighbour SRGAP2 (SLIT-ROBO Rho GTPase activating protein), as both genes have four paralogues in humans but only one vertebra-emerging orthologue in all other species. No species with two or three FAM72/SRGAP2 gene pairs could be identified, and the four exclusively human-defining ohnologues, with different mutation patterns in Homo neanderthalensis and Denisova hominin, may remain under epigenetic control through long non-coding (lnc) RNAs.

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“…14 Altered expression and function of mediator subunits have been implicated in various diseases. 15 For example, MED15, a subunit within the tail module, 14 serves as a target for different signaling pathways 16e18 and plays pathophysiologic roles in several human diseases, 19,20 including breast cancer. 21 We recently reported the implication of MED15 in castration-resistant prostate cancer and its direct link to transforming growth factor (TGF)-b signaling in this disease.…”

mentioning

confidence: 99%

Clinical and Molecular Implications of MED15 in Head and Neck Squamous Cell Carcinoma

Shaikhibrahim¹,

Offermann²,

Halbach³

et al. 2015

The American Journal of Pathology

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Head and neck squamous cell carcinoma (HNSCC) progression depends on various dysregulated pathways. Regulation of diverse pathways is mediated by the mediator complex. The mediator subunit MED15 is essential for transforming growth factor (TGF)-β signaling and involved in breast and prostate cancers. We investigated the implication of MED15 in HNSCC. IHC for MED15 was performed on 324 tissue samples, and TGF-β assessed the use of Ki-67 and pSMAD3 as markers. MED15 knockdown followed by proliferation and migration assays, as well as TGF-β1 treatment followed by MED15 analysis, was also performed. MED15 was overexpressed in 35% of primary tumors, 30% of lymph node metastases, and 70% of recurrences in contrast to no or low expression in benign tumors. MED15 overexpression in primary tumors from patients who developed recurrences was associated with higher mortality rates and occurred at highest frequency in oral cavity or oropharyngeal tumors. Furthermore, MED15 expression correlated between primary tumors and corresponding lymph node metastases. MED15 correlated with proliferation in tissues, and MED15 knockdown reduced proliferation and migration. We observed an association between MED15 and TGF-β activity in tissues because TGF-β activation led to increased MED15 expression and reduced pSMAD3 on MED15 knockdown. Taken together, our results implicate MED15 in HNSCC and hint that MED15 overexpression is a clonal event during HNSCC progression. MED15 may serve as a prognostic marker for recurrence and as a therapeutic target.

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Unraveling framework of the ancestral Mediator complex in human diseases

Cited by 49 publications

References 121 publications

Characterization of the Influence of Mediator Complex in HIV-1 Transcription

Characterization of the Influence of Mediator Complex in HIV-1 Transcription

All-or-(N)One – an epistemological characterization of the human tumorigenic neuronal paralogous FAM72 gene loci

Clinical and Molecular Implications of MED15 in Head and Neck Squamous Cell Carcinoma

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