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P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway

ABSTRACT: P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway

PROVIDER: PRJNA894501 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22047300.fastq.gz	Fastqsanger.gz
	SRR22047301.fastq.gz	Fastqsanger.gz
	SRR22047302.fastq.gz	Fastqsanger.gz
	SRR22047303.fastq.gz	Fastqsanger.gz
	SRR22047304.fastq.gz	Fastqsanger.gz

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Similar Datasets

P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway

Project description:We used RNA sequencing to deciphere a molecular basis for the synthethic lethality of non-genotoxic p53 activation and P-TEFb inhibition.

2022-12-30 | GSE216610 | GEO

P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway.

Project description:Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target in cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting of P-TEFb shall benefit when deployed as a combination therapy. We screened a comprehensive oncology library and identified clinically relevant antimetabolites and Mouse double minute 2 homolog (MDM2) inhibitors as top compounds eliciting p53-dependent death of colorectal cancer cells in synergy with selective inhibitors of P-TEFb. While the targeting of P-TEFb augments apoptosis by anti-metabolite 5-fluorouracil, it switches the fate of cancer cells by the non-genotoxic MDM2 inhibitor Nutlin-3a from cell-cycle arrest to apoptosis. Mechanistically, the fate switching is enabled by the induction of p53-dependent pro-apoptotic genes and repression of P-TEFb-dependent pro-survival genes of the PI3K-AKT signaling cascade, which stimulates caspase 9 and intrinsic apoptosis pathway in BAX/BAK-dependent manner. Finally, combination treatments trigger apoptosis of cancer cell spheroids. Together, co-targeting of P-TEFb and suppressors of intrinsic apoptosis could become a viable strategy to eliminate cancer cells.

| S-EPMC9976905 | biostudies-literature

Inhibition of CDK12 induces cancer cell dependence on activated P-TEFb via the ATM-stimulated p53 and NF-kB transcriptional programs

Project description:P-TEFb and CDK12 facilitate transcription elongation by RNA polymerase II and play prominent roles in cancer. Understanding their functional interplay could inform novel anti-cancer strategies. While inhibition of CDK12 downregulates unique sets of genes, eliciting genomic instability that is being exploited for novel therapies, little is known about the significance of transcriptional induction in CDK12-targeted cells. We show that inhibition of CDK12 in colon cancer-derived cells activates P-TEFb and induces genes of key cancer signaling pathways, including p53 and NF-kB. Mechanistically, cancer cells become exquisitely dependent on P-TEFb through activation of p53-dependent apoptosis and attenuation of NF-kB-dependent proliferation. Furthermore, we show that the DNA damage-responsive ATM kinase mediates these effects. While ATM is required for the synthetic lethality of CDK12 and P-TEFb co-targeting in p53-proficient cells, co-inhibition of ATM and CDK12 synergizes in decreasing viability of p53-deficient cells. Finally, pairwise targeting of CDK12, P-TEFb and transcription initiation kinase CDK7 stimulates p53-dependent apoptosis of cancer cell spheroids. We propose that the stimulation of Pol II pause release by P-TEFb at the signal-responsive genes underlies the dependence of CDK12-targeted cancer cells on P-TEFb. Together, our work provides a rationale for combinatorial targeting of CDK12 and P-TEFb or the induced oncogenic pathways in cancer.

2023-09-17 | GSE236803 | GEO

RBM7 activates P-TEFb for a pro-survival transcriptional response to DNA damage

Project description:DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain obscure. Here we show that following DNA damage, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) elongation and increases cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by DNA damage-enhanced binding of RBM7 to 7SK, the scaffold of the 7SK small nuclear ribonucleoprotein (snRNP) that inhibits P-TEFb. As a result, P-TEFb relocates from 7SK snRNP to chromatin to activate transcription of key DDR genes and multiple classes of non-coding RNAs. By alleviating the inhibition of P-TEFb, RBM7 thus promotes Pol II elongation to activate a transcriptional response that is crucial for cell fate upon genotoxic insult. Our work highlights a novel paradigm in stress-dependent control of Pol II pause release, and offers the promise of combating cancer by RBM7 and P-TEFb antagonists in combination with established DNA damage-inducing chemotherapeutics.

2018-06-01 | E-MTAB-6475 | biostudies-arrayexpress

SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

Project description:SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

| PRJNA796501 | ENA

P-TEFb function in ncRNA transcription

Project description:Many ncRNAs serve as regulatory molecules in various physiological pathways. Distinct from protein-coding RNA expression, ncRNA expression is regulated solely by transcription and RNA processing/stability. Transcriptional regulation in ncRNA genes is thus important to be understood and is yet to be known completely. Previously, we identified that a subset of mammalian ncRNA genes is transcriptionally regulated by RNA Pol II promoter-proximal pausing and in a tissue-specific manner. In this study, human stimulus-inducible ncRNA genes were monitored to assess the function of P-TEFb, a master Pol II pausing regulator for protein-coding genes, in ncRNA transcription. Our findings indicate that the expression of many ncRNA genes is regulated by P-TEFb. Interestingly, a biphasic characteristic of P-TEFb inhibition in serum responsive ncRNA genes was observed: S2 phospho-Pol II was largely increased in the TSS (–300 to +300) whereas overall, it was decreased in the gene body (> +350) upon chemical inhibition of P-TEFb. In addition, the three representative ncRNAs, MALAT1, NEAT1, and XIST, were further analyzed for determining P-TEFb association. Taken together, we propose the transcriptional activation of many human ncRNAs utilizing pausing and releasing Pol II and the regulatory mechanism of transcriptional elongation of these genes requiring the function of P-TEFb.

2018-07-31 | GSE117848 | GEO

P-TEFb function in ncRNA transcription

Project description:P-TEFb function in ncRNA transcription

| PRJNA483416 | ENA

Angiotensin IV attenuates diabetic cardiomyopathy via suppressing FoxO1-induced excessive autophagy, apoptosis and fibrosis

Project description:Angiotensin IV attenuates diabetic cardiomyopathy via suppressing FoxO1-induced excessive autophagy, apoptosis and fibrosis

| PRJNA660959 | ENA

Intrinsic Apoptosis Shapes the Tumor Spectrum Linked to Inactivation of the Deubiquitinase BAP1

Project description:Intrinsic Apoptosis Shapes the Tumor Spectrum Linked to Inactivation of the Deubiquitinase BAP1

| PRJNA493079 | ENA

The 7SK/P-TEFb snRNP controls ultraviolet radiation-induced transcriptional reprogramming

Project description:Releasing promoter-proximally-paused RNA polymerase II (RNAPII) by the positive transcription elongation factor b (P-TEFb) is a central regulatory step of eukaryotic mRNA synthesis. The nuclear activity of P-TEFb is controlled mainly by the 7SK small nuclear RNP (snRNP) which sequesters active P-TEFb into inactive 7SK/P-TEFb snRNP. Here we demonstrate that under normal culture conditions, the lack of 7SK snRNP has only a minor impact on global RNAPII transcription and promoter-proximal pausing without detectable consequences on cell growth and proliferation. However, upon ultraviolet (UV) light-induced DNA damage, cells lacking 7SK have a defective transcriptional response and highly reduced viability. Both UV-induced release of ‘lesion-scanning’ polymerases and activation of key early responsive genes are compromised in the absence of 7SK. We show that proper induction of 7SK-dependent UV-responsive genes, namely efficient release of paused RNAPII and recruitment of key elongation factors, requires P-TEFb activity directly mobilized from the nucleoplasmic 7SK/P-TEFb snRNP.

2021-03-30 | GSE147055 | GEO

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