P53 activation induces targetable dependence on FLIPL
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA453583 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7064480_1.fastq.gz | Fastqsanger.gz | |||
| SRR7064480_2.fastq.gz | Fastqsanger.gz | |||
| SRR7064490_1.fastq.gz | Fastqsanger.gz | |||
| SRR7064490_2.fastq.gz | Fastqsanger.gz | |||
| SRR7064481_1.fastq.gz | Fastqsanger.gz |
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Project description:A better understanding of how p53 differentially activates cell cycle arrest or cell death is important to maximize benefits of therapeutic strategies dependant by wild-type p53. Here, we report that activation of pro-apoptotic p53 transcriptional targets in colorectal cancer cells imposes a critical, targetable dependence on the long splice form of the caspase-8 regulator FLIP (FLIPL) for survival. Upon Nutlin-3A induced stabilisation p53 directly upregulates FLIPL expression in a manner dependent on Class-I HDAC activity. Preventing FLIPL upregulation with the clinically relevant Class-I selective inhibitor Entinostat promotes apoptosis in response to Nutlin-3A , which predominantly induces growth arrest despite upregulating a range of pro-apoptotic target genes. Cell death in response to Nutlin-3A in FLIPL-depleted cells is mediated through two of p53's canonical transcriptional targets TRAIL-R2 and BAX and is caspase-8-dependent. This work uncovers novel, clinically relevant biology that identifies FLIPL as a key target for overcoming resistance to p53-activating agents.
2020-04-25 | GSE113682 | GEO
Project description:Streptozotocin induces renal proximal tubular injury through p53 signaling activation
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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
Project description:RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia
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Project description:Heat shock transcription factor 1 (HSF1) regulates the expression of a wide array of genes, controlling expression of heat shock proteins (HSPs) and cell growth. Although acute depletion of HSF1 induces cellular senescence, the underlying mechanisms are poorly understood. Here, we report that HSF1 depletion-induced senescence (HDIS) of human diploid fibroblasts (HDFs) was independent of HSP-mediated proteostasis, but dependent on activation of the p53-p21 pathway, partly because of increased expression of dehydrogenase/reductase 2 (DHRS2), a putative MDM2 inhibitor. We observed that HDIS occurred without decreased levels of major HSPs or increased proteotoxic stress in HDFs. Additionally, an inhibitor of HSP70 family proteins increased proteotoxicity and suppressed cell growth, but failed to induce senescence. Importantly, we found that activation of the p53-p21 pathway due to reduced MDM2-dependent p53 degradation was required for HDIS. Furthermore, we provide evidence that increased DHRS2 expression contribute to p53 stabilization and HDIS. Collectively, our observations uncovered a molecular pathway in which HSF1 depletion-induced DHRS2 expression leads to activation of the MDM2-p53-p21 pathway required for HDIS.
2018-05-01 | GSE111355 | GEO
Project description:As a critical cellular stress sensor, p53 mediates a variety of defensive processes including cell-cycle arrest, apoptosis, and senescence to prevent propagation of hyperproliferative cells or cells with a damaged genome, hence the formation of neoplasia. Transactivation of downstream genes plays an important while sometimes controversial role in regulating these cellular processes. To evaluate the dependence on transcriptional activation in p53’s activities, we generated genetically-modified mouse lines carrying mutations in the transactivation domains (TADs) of p53. These transactivatio-deficient mutants serve as unique reagents to probe the dependence on robust transactivation in p53-mediated cellular functions, as well as the underneath mechanisms. To identify genes differentially regulated by these p53 mutants, we performed gene expression profiling analysis on mouse embryonic fibroblast cells (MEFs) from these mice in the context of oncogenic Ras-induced premature cellular senescence. Mouse embryonic fibroblasts (MEFs) with different p53 genotypes were infected with retroviral H-Ras V12, which induces premature cellular senescence in p53 wild-type MEFs but not in p53 null MEFs. 5 genotypic groups of MEFs were used in the study: (i) p53L25Q/W26S, or "25,26", in which the first TAD (transactivation domain) of p53 is disrupted by the mutation, 5 biological samples; (ii) p53W53Q/F54S, or "53,54", in which the second TAD of p53 is disrupted by the mutation, 3 biological samples; (iii) p53L25Q/W26S/W53Q/F54S, or "QM", in which both TADs or p53 are disrupted, 3 biological samples; (iv) p53 wild-type, or "WT", 6 biological samples; (v) p53 null, or "Null", 6 biological samples.
2011-05-13 | E-GEOD-27901 | biostudies-arrayexpress
Project description:IL-11 induces NLRP3 inflammasome activation
| PRJNA978574 | ENA
Project description:Background and Aims: p53 can limit the self-renewal of stem cells from various tissues. Experimental evidence suggests that deletion of p53 can cooperate with other oncogenic events to induce aberrant self-renewal and transformation of progenitor cells. It is not known whether p53 deletion alone can lead to liver tumor formation. Methods: We used AlfpCre mice for liver-specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms. Liver tumors derived from Trp53 KO mice, liver tumors from DEN-treated wildtype mice, Trp53 KO liver and wildtype liver were isolated and RNA was extracted. Agilent-026655 Mouse 4x44K v2 arrays were used.
2011-12-29 | E-GEOD-34760 | biostudies-arrayexpress
Project description:Inhibition of CDK12 induces cancer cell dependence on activated P-TEFb via the ATM-stimulated p53 and NF-kB transcriptional programs
| PRJNA992457 | ENA
Project description:Frequent 4EBP1 amplification induces synthetic dependence on FGFR signaling in cancer
| PRJNA811788 | ENA