HIF1A Employs CDK8-Mediator to Stimulate RNAPII Elongation in Response to Hypoxia

Galbraith, Matthew D.; Allen, Mary A.; Bensard, Claire; Wang, Xiaoxing; Schwinn, Marie K.; Qin, Bo; Long, Henry W.; Daniels, Danette L.; Hahn, William C.; Dowell, Robin D.; Espinosa, Joaquín M.

doi:10.1016/j.cell.2013.04.048

Cited by 308 publications

(387 citation statements)

References 51 publications

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“…Indeed, HIF1␣ associates directly with CDK8, MED12, and MED13, which comprise the kinase module of the Mediator (35), indicating that hypoxic signals are channeled through the kinase module. Among the components of the kinase module, MED12 interacts with aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner shared by HIF1␣ and the aryl hydrocarbon receptor (AHR) that is indispensable for the AHR-dependent xenobiotic response as well as the HIF-dependent hypoxic response (36).…”

Section: Discussionmentioning

confidence: 99%

The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression

Sekine

Okazaki

Ota

et al. 2016

Molecular and Cellular Biology

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The KEAP1-NRF2 system plays a central role in cytoprotection. NRF2 is stabilized in response to electrophiles and activates transcription of antioxidant genes. Although robust induction of NRF2 target genes confers resistance to oxidative insults, how NRF2 triggers transcriptional activation after binding to DNA has not been elucidated. To decipher the molecular mechanisms underlying NRF2-dependent transcriptional activation, we purified the NRF2 nuclear protein complex and identified the Mediator subunits as NRF2 cofactors. Among them, MED16 directly associated with NRF2. Disruption of Med16 significantly attenuated the electrophile-induced expression of NRF2 target genes but did not affect hypoxia-induced gene expression, suggesting a specific requirement for MED16 in NRF2-dependent transcription. Importantly, we found that 75% of NRF2-activated genes exhibited blunted inductions by electrophiles in Med16-deficient cells compared to wild-type cells, which strongly argues that MED16 is a major contributor supporting NRF2-dependent transcriptional activation. NRF2-dependent phosphorylation of the RNA polymerase II C-terminal domain was absent in Med16-deficient cells, suggesting that MED16 serves as a conduit to transmit NRF2-activating signals to RNA polymerase II. MED16 indeed turned out to be essential for cytoprotection against oxidative insults. Thus, the KEAP1-NRF2-MED16 axis has emerged as a new regulatory pathway mediating the antioxidant response through the robust activation of NRF2 target genes.

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Section: Discussionmentioning

confidence: 99%

The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression

Sekine

Okazaki

Ota

et al. 2016

Molecular and Cellular Biology

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“…We have now tested the effects of hypoxia and Senexin B treatment of HEK293 cells on four genes found in a previous study (7) to be strongly induced by hypoxia and regulated by CDK8 in HCT116. Induction of one of these genes, ANKRD37, was attenuated by Senexin B (Fig.…”

Section: Cdk8/19 Inhibition Preferentially Affects Nfκb Induction Ofmentioning

confidence: 99%

“…A key function of CDK8/19 is phosphorylation of the C-terminal domain (CTD) of RNA Pol II, enabling elongation of the transcription; CDK8/19 exert this activity not globally, but rather only in the context of genes that become activated by transcription-inducing factors (6)(7)(8). CDK8/19 regulation is especially pertinent in cancers, where CDK8 positively regulates several cancer-relevant signaling pathways (5), including Wnt/β-catenin (9), the serum response network (6), TGFβ (10), HIF1α (7), and estrogen receptor (8).…”

Section: Significancementioning

confidence: 99%

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

Chen

Liang

Jiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

130

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The nuclear factor-κB (NFκB) family of transcription factors has been implicated in inflammatory disorders, viral infections, and cancer. Most of the drugs that inhibit NFκB show significant side effects, possibly due to sustained NFκB suppression. Drugs affecting induced, but not basal, NFκB activity may have the potential to provide therapeutic benefit without associated toxicity. NFκB activation by stress-inducible cell cycle inhibitor p21 was shown to be mediated by a p21-stimulated transcription-regulating kinase CDK8. CDK8 and its paralog CDK19, associated with the transcriptional Mediator complex, act as coregulators of several transcription factors implicated in cancer; CDK8/19 inhibitors are entering clinical development. Here we show that CDK8/19 inhibition by different small-molecule kinase inhibitors or shRNAs suppresses the elongation of NFκB-induced transcription when such transcription is activated by p21-independent canonical inducers, such as TNFα. On NFκB activation, CDK8/19 are corecruited with NFκB to the promoters of the responsive genes. Inhibition of CDK8/19 kinase activity suppresses the RNA polymerase II C-terminal domain phosphorylation required for transcriptional elongation, in a gene-specific manner. Genes coregulated by CDK8/19 and NFκB includeIL8,CXCL1, andCXCL2, which encode tumor-promoting proinflammatory cytokines. Although it suppressed newly induced NFκB-driven transcription, CDK8/19 inhibition in most cases had no effect on the basal expression of NFκB-regulated genes or promoters; the same selective regulation of newly induced transcription was observed with other transcription signals potentiated by CDK8/19. This selective role of CDK8/19 identifies these kinases as mediators of transcriptional reprogramming, a key aspect of development and differentiation as well as pathological processes.

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“…ChIP was performed as described before (Galbraith et al 2013) and described in detail in the Supplemental Methods. Briefly, after drug or vehicle treatment, cells were cross-linked using 1% formaldehyde, washed twice with cold PBS, lysed in RIPA buffer, and cell lysates sonicated.…”

Section: Chip-seqmentioning

confidence: 99%

Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity

et al. 2017

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The tumor suppressor TP53 is the most frequently mutated gene product in human cancer. Close to half of all solid tumors carry inactivating mutations in the TP53 gene, while in the remaining cases, TP53 activity is abrogated by other oncogenic events, such as hyperactivation of its endogenous repressors MDM2 or MDM4. Despite identification of hundreds of genes regulated by this transcription factor, it remains unclear which direct target genes and downstream pathways are essential for the tumor suppressive function of TP53. We set out to address this problem by generating multiple genomic data sets for three different cancer cell lines, allowing the identification of distinct sets of TP53-regulated genes, from early transcriptional targets through to late targets controlled at the translational level. We found that although TP53 elicits vastly divergent signaling cascades across cell lines, it directly activates a core transcriptional program of ∼100 genes with diverse biological functions, regardless of cell type or cellular response to TP53 activation. This core program is associated with high-occupancy TP53 enhancers, high levels of paused RNA polymerases, and accessible chromatin. Interestingly, two different shRNA screens failed to identify a single TP53 target gene required for the anti-proliferative effects of TP53 during pharmacological activation in vitro. Furthermore, bioinformatics analysis of thousands of cancer genomes revealed that none of these core target genes are frequently inactivated in tumors expressing wild-type TP53. These results support the hypothesis that TP53 activates a genetically robust transcriptional program with highly distributed tumor suppressive functions acting in diverse cellular contexts.

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HIF1A Employs CDK8-Mediator to Stimulate RNAPII Elongation in Response to Hypoxia

Cited by 308 publications

References 51 publications

The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression

The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity

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