Acute HSF1 depletion induces cellular senescence through activation of the MDM2-p53-p21 pathway in human diploid fibroblasts
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA436708 | ENA |
REPOSITORIES: ENA
Similar Datasets
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:KT-253 is a potent and selective heterobifunctional MDM2 degrader with superior activity to MDM2/p53 small molecule inhibitors. RS4;11 cells treated with KT-253 indicated no off-target protein degradation. All significantly upregulated proteins are p53 and its target genes. KT-253 overcomes p53/MDM2 feedback loop. Targeted proteomics analysis of MDM2 levels in RS4;11 cells shows that KT-253 (150 nM KT-253 for 15 minutes) can achieve greater than 90% degradation of MDM2 within 1 hour posttreatment, whereas MDM2 levels continued to increase 1 hour after treatment with DS-3032 A single dose of KT-253 drives sustained tumor regression in ALL xenografts. Targeted proteomic analysis of tumors demonstrates robust degradation of MDM2 1-hour post dosing with KT-253. This is associated with activation of the p53 pathway as evidenced by a corresponding upregulation of proteomics biomarkers p53, p21, and PHLDA3.
2025-05-07 | PXD057859 | Pride
Project description:Mice on two different ketogenic diets induce p53 and cellular senescence in multiple organs, including heart and kidney. This is mediated through inactivation of MDM2 by caspase-2 cleavage, leading to p53 accumulation and induction of p21. Ketogenic diet also induced pAMPK, suggesting that persistent activation leads to p53-dependent senescence.
2024-04-12 | GSE233831 | GEO
Project description:p53 is a transcription factor that plays a critical role in cancer prevention. However, the mechanisms by which p53 exerts its tumor-suppressive function is still unclear. While PUMA/BBC3 and NOXA/PMAIP1 are known to be important in p53-dependent apoptosis, and p21/CDKN1A is crucial for p53-dependent cell-cycle arrest, we demonstrate that zebrafish lacking puma, noxa, and p21 do not show a predisposition to cancer. This suggests that additional p53 transcriptional targets are sufficient for its tumor suppressive function. Contrary to the prevailing belief that p21 is the key regulator of p53-dependent cell-cycle arrest, we provide evidence that p53 can still induce cell-cycle arrest in the absence of p21, following DNA damage or loss of mdm2 (p53 activation in the absence of stress). This implies the involvement of other p53 transcriptional targets in mediating p53-dependent cell-cycle arrest. Since p53 tumor suppression is conserved across multiple vertebrate species, we conducted a cross-species comparative analysis of p53-dependent transcriptional profiles to identify a conserved set of 136 p53-upregulated transcripts. Our analysis stresses the importance of ortholog to paralog analysis across species, since in many cases the paralog but not ortholog in differing species is p53 dependent. Additionally, we performed a CRISPR/Cas9 G0 “crispant” screen in a genetic background lacking mdm2, puma, noxa, and p21 to identify key components involved in p53-dependent cell-cycle arrest. Our findings revealed that ccng1, fbxw7, and foxo3b play an important role in this process.
2025-06-16 | GSE288667 | GEO
Project description:p53 is a transcription factor that plays a critical role in cancer prevention. However, the mechanisms by which p53 exerts its tumor-suppressive function is still unclear. While PUMA/BBC3 and NOXA/PMAIP1 are known to be important in p53-dependent apoptosis, and p21/CDKN1A is crucial for p53-dependent cell-cycle arrest, we demonstrate that zebrafish lacking puma, noxa, and p21 do not show a predisposition to cancer. This suggests that additional p53 transcriptional targets are sufficient for its tumor suppressive function. Contrary to the prevailing belief that p21 is the key regulator of p53-dependent cell-cycle arrest, we provide evidence that p53 can still induce cell-cycle arrest in the absence of p21, following DNA damage or loss of mdm2 (p53 activation in the absence of stress). This implies the involvement of other p53 transcriptional targets in mediating p53-dependent cell-cycle arrest. Since p53 tumor suppression is conserved across multiple vertebrate species, we conducted a cross-species comparative analysis of p53-dependent transcriptional profiles to identify a conserved set of 136 p53-upregulated transcripts. Our analysis stresses the importance of ortholog to paralog analysis across species, since in many cases the paralog but not ortholog in differing species is p53 dependent. Additionally, we performed a CRISPR/Cas9 G0 “crispant” screen in a genetic background lacking mdm2, puma, noxa, and p21 to identify key components involved in p53-dependent cell-cycle arrest. Our findings revealed that ccng1, fbxw7, and foxo3b play an important role in this process.
2025-06-16 | GSE288666 | GEO
Project description:p53 is a transcription factor that plays a critical role in cancer prevention. However, the mechanisms by which p53 exerts its tumor-suppressive function is still unclear. While PUMA/BBC3 and NOXA/PMAIP1 are known to be important in p53-dependent apoptosis, and p21/CDKN1A is crucial for p53-dependent cell-cycle arrest, we demonstrate that zebrafish lacking puma, noxa, and p21 do not show a predisposition to cancer. This suggests that additional p53 transcriptional targets are sufficient for its tumor suppressive function. Contrary to the prevailing belief that p21 is the key regulator of p53-dependent cell-cycle arrest, we provide evidence that p53 can still induce cell-cycle arrest in the absence of p21, following DNA damage or loss of mdm2 (p53 activation in the absence of stress). This implies the involvement of other p53 transcriptional targets in mediating p53-dependent cell-cycle arrest. Since p53 tumor suppression is conserved across multiple vertebrate species, we conducted a cross-species comparative analysis of p53-dependent transcriptional profiles to identify a conserved set of 136 p53-upregulated transcripts. Our analysis stresses the importance of ortholog to paralog analysis across species, since in many cases the paralog but not ortholog in differing species is p53 dependent. Additionally, we performed a CRISPR/Cas9 G0 “crispant” screen in a genetic background lacking mdm2, puma, noxa, and p21 to identify key components involved in p53-dependent cell-cycle arrest. Our findings revealed that ccng1, fbxw7, and foxo3b play an important role in this process.
2025-06-16 | GSE288660 | GEO
Project description:p53 is a transcription factor that plays a critical role in cancer prevention. However, the mechanisms by which p53 exerts its tumor-suppressive function is still unclear. While PUMA/BBC3 and NOXA/PMAIP1 are known to be important in p53-dependent apoptosis, and p21/CDKN1A is crucial for p53-dependent cell-cycle arrest, we demonstrate that zebrafish lacking puma, noxa, and p21 do not show a predisposition to cancer. This suggests that additional p53 transcriptional targets are sufficient for its tumor suppressive function. Contrary to the prevailing belief that p21 is the key regulator of p53-dependent cell-cycle arrest, we provide evidence that p53 can still induce cell-cycle arrest in the absence of p21, following DNA damage or loss of mdm2 (p53 activation in the absence of stress). This implies the involvement of other p53 transcriptional targets in mediating p53-dependent cell-cycle arrest. Since p53 tumor suppression is conserved across multiple vertebrate species, we conducted a cross-species comparative analysis of p53-dependent transcriptional profiles to identify a conserved set of 136 p53-upregulated transcripts. Our analysis stresses the importance of ortholog to paralog analysis across species, since in many cases the paralog but not ortholog in differing species is p53 dependent. Additionally, we performed a CRISPR/Cas9 G0 “crispant” screen in a genetic background lacking mdm2, puma, noxa, and p21 to identify key components involved in p53-dependent cell-cycle arrest. Our findings revealed that ccng1, fbxw7, and foxo3b play an important role in this process.
2025-06-16 | GSE288659 | GEO
Project description:The heat-shock protein 90 (HSP90) is a promising target in cancer therapy, but its inhibitors' clinical trial failures are partly due to a compensatory heat-shock response (HSR) mediated by heat-shock factor 1 (HSF1). We previously showed that wildtype p53 reduces HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we explore if simultaneous p53 activation or cell cycle inhibition can disrupt the HSF1-HSR axis and enhance HSP90 inhibitors' efficiency. mRNA sequencing was performed on HCT116 cells treated for 24 hours with DMSO, 50 nM Ganetespib, 1 µM RG-7388, or their combination. We found that the p53 activator Idasanutlin suppresses HSF1-HSR activity in HSP90 inhibitor-based therapies, synergistically reducing cell viability and accelerating cell death in p53-proficient colorectal cancer (CRC) cells and organoids. Combination therapy upregulates p53 pathways, apoptosis, and inflammation. In a CRC mouse model, dual HSF1-HSP90 inhibition represses tumor growth and alters immune cell composition. CDK4/6 inhibition under HSP90 inhibition mimics HSR repression in p53-proficient CRC cells. In p53-deficient CRC cells and p53-mutated organoids, combined HSP90 and CDK4/6 inhibition suppresses HSF1-HSR and reduces cancer growth, offering a p53-independent strategy for CRC treatment. In conclusion, we present new options to improve HSP90-based therapies for enhanced CRC treatment.
2025-03-28 | E-MTAB-14877 | biostudies-arrayexpress
Project description:CDK4 inhibitors have reached clinical approval for cancer therapy. In parallel, the p53 antagonist Mdm2 remains an attractive target for anti-cancer therapy, including numerous clinical studies. The genes encoding Mdm2 and CDK4 are frequently co-amplified in human malignancies, most notably in liposarcomas, suggesting their combined targeting for therapy. Here we show, however, that small compounds that inhibit Mdm2 and CDK4 antagonize each other rather than synergize in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon Mdm2 inhibition, and similar results were obtained when depleting Mdm2 and/or CDK4 with siRNA. CDK4 inhibitors also interfered with p53 activity in response to DNA damage. CDK4 inhibition did not reduce p53 binding or histone acetylation to promoters, but rather attenuated the subsequent recruitment of RNA polymerase II. The complexes of p53 and Mdm2, as well as CDK4 and Cyclin D1, physically associated with each other. Upon combined inhibition of Mdm2 and CDK4/6, the interaction of this complex was impaired. Thus, the CDK4-Cyclin D1 complex plays a key role in enabling the transcription of p53 target genes. Taken together, our results raise caution regarding the combination of CDK4 inhibitors with Mdm2 antagonists or conventional DNA-damaging chemotherapeutics in the clinics. Moreover, they suggest a hitherto unknown role for CDK4-cyclin D1 complex in sustaining p53 activity, possibly focusing p53-mediated transcription on actively proliferating cells.
2018-09-20 | GSE113369 | GEO
Project description:Upon heat shock, Hsf1 protein is extensively phosphorylated, however, this modification is inhibited by an hsf1-bal mutation. To get genome-wide effect of the hyperphosphorylation on Hsf1-regulated transcription, the heat-induced gene expression profiles in HSF1 and hsf1-bal cells were compared. Keywords: stress response
2005-09-27 | GSE3361 | GEO