Abstract:Nuclear all-trans retinoic acid receptors (RARs) initiate early transcriptional events which engage pluripotent cells to differentiate into specific lineages. RAR-controlled transactivation depends mostly on agonist-induced structural transitions in RAR C-terminus (AF-2), thus bridging coactivators or corepressors to chromatin, hence controlling preinitiation complex assembly. However, the contribution of other domains of RAR to its overall transcriptional activity remains poorly defined. A proteomic character… Show more
“…The SEC can interact with a subset of co-activators such as Mediator, polymerase-associated factor 1 (PAF1) and Integrator, the latter of which is a complex that interacts with the CTD of Pol II 60,79–82 . Moreover, the SEC can also colocalize with BRD4 at gene promoters 83 . The SEC and BRD4 predominantly mediate the recruitment P-TEFb, but their regulatory importance and composition with regard to paused Pol II release seems to vary across different genes, cell types and stimuli.…”
Section: Factors Involved In the Release Of Paused Pol IImentioning
Recent advances in sequencing techniques that measure nascent transcripts and that reveal the positioning of RNA polymerase II (Pol II) have shown that the pausing of Pol II in promoter-proximal regions and its release to initiate a phase of productive elongation are key steps in transcription regulation. Moreover, after the release of Pol II from the promoter-proximal region, elongation rates are highly dynamic throughout the transcription of a gene, and vary on a gene-by-gene basis. Interestingly, Pol II elongation rates affect co-transcriptional processes such as splicing, termination and genome stability. Increasing numbers of factors and regulatory mechanisms have been associated with the steps of transcription elongation by Pol II, revealing that elongation is a highly complex process. Elongation is thus now recognized as a key phase in the regulation of transcription by Pol II.
“…The SEC can interact with a subset of co-activators such as Mediator, polymerase-associated factor 1 (PAF1) and Integrator, the latter of which is a complex that interacts with the CTD of Pol II 60,79–82 . Moreover, the SEC can also colocalize with BRD4 at gene promoters 83 . The SEC and BRD4 predominantly mediate the recruitment P-TEFb, but their regulatory importance and composition with regard to paused Pol II release seems to vary across different genes, cell types and stimuli.…”
Section: Factors Involved In the Release Of Paused Pol IImentioning
Recent advances in sequencing techniques that measure nascent transcripts and that reveal the positioning of RNA polymerase II (Pol II) have shown that the pausing of Pol II in promoter-proximal regions and its release to initiate a phase of productive elongation are key steps in transcription regulation. Moreover, after the release of Pol II from the promoter-proximal region, elongation rates are highly dynamic throughout the transcription of a gene, and vary on a gene-by-gene basis. Interestingly, Pol II elongation rates affect co-transcriptional processes such as splicing, termination and genome stability. Increasing numbers of factors and regulatory mechanisms have been associated with the steps of transcription elongation by Pol II, revealing that elongation is a highly complex process. Elongation is thus now recognized as a key phase in the regulation of transcription by Pol II.
Promoter-proximal pausing by RNA polymerase II (Pol II) is a well-established mechanism to control the timing, rate, and possibly the magnitude of transcriptional responses. Recent studies have shown that cellular signaling pathways can regulate gene transcription and signaling outcomes by controlling Pol II pausing in a wide array of biological systems. Identification of the proteins and small molecules that affect the establishment and release of paused Pol II is shedding new light on the mechanisms and biology of Pol II pausing. This review will focus on the interplay between cellular signaling pathways and Pol II pausing during normal development and under disease conditions.
“…For activation of P-TEFb, BRD4 competes with inhibitory complex HEXIM/7SK and is recruited to transcription start site via histone acetylation. SEC may co-localize with BRD4 at gene promoters and interact with coactivators such as the Mediator and polymerase-associated factor 1 (PAF1) (Flajollet et al 2013). Ultimately, the recruitment of these cofactors depends on TFs that bind to promoters or enhancers.…”
Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and antiapoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.
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