Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

AbstractA prerequisite for gain-of-function (GOF) p53 missense mutants (mutp53) is protein stabilization. Moreover, a prerequisite for mutp53 stabilization is loss of the remaining wildtype (WT) p53 allele (loss-of-heterozygosity, p53LOH) in mutp53/+ tumors. Thus, GOF, mutp53 stabilization and p53LOH are strictly linked. However, the driving force for p53LOH is unknown. Typically, heterozygous tumors are an instable transition state. Here we identify the repressive WTp53-HSF1 axis as the driver of p53LOH.We find that the WTp53 allele in AOM/DSS-induced colorectal tumors (CRC) of p53R248Q/+ mice retains its haploid transcriptional activity. Notably, WTp53 represses heat-shock factor 1 (HSF1) activity, the master transcription factor of the proteotoxic stress defense response (HSR) that is ubiquitously and constitutively activated in cancer tissues. HSR is critical for stabilizing oncogenic proteins including mutp53. WTp53-retaining murine CRC tumors and tumor-derived organoids and human CRC cells all suppress the tumor-promoting HSF1 transcriptional program.Mechanistically, the retained WTp53 allele activates CDKN1A/p21, leading to cell cycle inhibition and suppression of the E2F target gene MLK3. MLK3 links cell cycle to the MAPK stress pathway to activate the HSR response. We show that in p53R248Q/+ tumors WTp53 activation by constitutive stress (emanating from proliferative/metabolic stresses and genomic instability) represses MLK3, consequently inactivating the MAPK-HSF1 response necessary to ensure tumor survival. This creates strong selection pressure for p53LOH which eliminates the repressive WTp53-HSF1 axis and unleashes the tumor-promoting HSF1 functions, inducing mutp53 stabilization and enabling invasion.HIGHLIGHTSheterozygous p53R248Q/+ tumors retain p53 transcriptional activity in a mouse model of colorectal cancer (CRC)wildtype p53 actively represses the tumor-promoting HSF1-regulated chaperone system and proteotoxic stress responsethe repressive WTp53 – HSF1 axis creates a selective pressure for WTp53 loss-of-heterozygosity in CRC tumorsp53 loss-of-heterozygosity enables stabilization of the gain-of-function p53R248Q mutant protein which in turn enables CRC invasion

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Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Nature Communications ◽

10.1038/s41467-021-24064-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Tamara Isermann ◽

Özge Çiçek Şener ◽

Adrian Stender ◽

Luisa Klemke ◽

Nadine Winkler ◽

...

Keyword(s):

Cell Cycle ◽

Loss Of Heterozygosity ◽

Driving Forces ◽

Heat Shock Factor 1 ◽

Proteotoxic Stress ◽

Chemically Induced ◽

Tumor Survival ◽

Cell Cycle Inhibition ◽

Partial Activity ◽

Stress Pathway

AbstractThe vast majority of human tumors with p53 mutations undergo loss of the remaining wildtype p53 allele (loss-of-heterozygosity, p53LOH). p53LOH has watershed significance in promoting tumor progression. However, driving forces for p53LOH are poorly understood. Here we identify the repressive WTp53–HSF1 axis as one driver of p53LOH. We find that the WTp53 allele in AOM/DSS chemically-induced colorectal tumors (CRC) of p53R248Q/+ mice retains partial activity and represses heat-shock factor 1 (HSF1), the master regulator of the proteotoxic stress response (HSR) that is ubiquitously activated in cancer. HSR is critical for stabilizing oncogenic proteins including mutp53. WTp53-retaining CRC tumors, tumor-derived organoids and human CRC cells all suppress the tumor-promoting HSF1 program. Mechanistically, retained WTp53 activates CDKN1A/p21, causing cell cycle inhibition and suppression of E2F target MLK3. MLK3 links cell cycle with the MAPK stress pathway to activate the HSR response. In p53R248Q/+ tumors WTp53 activation by constitutive stress represses MLK3, thereby weakening the MAPK-HSF1 response necessary for tumor survival. This creates selection pressure for p53LOH which eliminates the repressive WTp53-MAPK-HSF1 axis and unleashes tumor-promoting HSF1 functions, inducing mutp53 stabilization enabling invasion.

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HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

10.1101/207001 ◽

2017 ◽

Author(s):

Toshiki Kijima ◽

Thomas L. Prince ◽

Megan L. Tigue ◽

Kendrick H. Yim ◽

Harvey Schwartz ◽

...

Keyword(s):

Heat Shock ◽

Transcriptional Activity ◽

Transcriptional Response ◽

Heat Shock Protein 90 ◽

Heat Shock Factor 1 ◽

Hsp90 Inhibitors ◽

Dynamic Modulation ◽

Proteotoxic Stress ◽

Significant Prolongation

AbstractHeat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.

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Faculty Opinions recommendation of An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1022503.256641 ◽

2004 ◽

Author(s):

Arp Schnittger

Keyword(s):

Cell Cycle ◽

Cell Cycle Inhibition

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Effects of 4E-BP1 expression on hypoxic cell cycle inhibition and tumor cell proliferation and survival

Cancer Biology & Therapy ◽

10.4161/cbt.7.9.6426 ◽

2008 ◽

Vol 7 (9) ◽

pp. 1441-1449 ◽

Cited By ~ 24

Author(s):

Bryan C. Barnhart ◽

Jennifer C. Lam ◽

Regina M. Young ◽

Peter J. Houghton ◽

Brian Keith ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Tumor Cell ◽

Hypoxic Cell ◽

Tumor Cell Proliferation ◽

Cell Cycle Inhibition

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The cell type-specific effect of TAp73 isoforms on the cell cycle and apoptosis

Cellular & Molecular Biology Letters ◽

10.2478/s11658-008-0011-z ◽

2008 ◽

Vol 13 (3) ◽

Cited By ~ 9

Author(s):

Jitka Holcakova ◽

Pavla Ceskova ◽

Roman Hrstka ◽

Petr Muller ◽

Lenka Dubska ◽

...

Keyword(s):

Cell Cycle ◽

Cancer Patients ◽

Transcriptional Activity ◽

Human Cancer ◽

Binding Capacity ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Specific Effect ◽

P53 Family ◽

Null Cell

Abstractp73, a member of the p53 family, exhibits activities similar to those of p53, including the ability to induce growth arrest and apoptosis. p73 influences chemotherapeutic responses in human cancer patients, in association with p53. Alternative splicing of the TP73 gene produces many p73 C- and N-terminal isoforms, which vary in their transcriptional activity towards p53-responsive promoters. In this paper, we show that the C-terminal spliced isoforms of the p73 protein differ in their DNA-binding capacity, but this is not an accurate predictor of transcriptional activity. In different p53-null cell lines, p73β induces either mitochondrial-associated or death receptor-mediated apoptosis, and these differences are reflected in different gene expression profiles. In addition, p73 induces cell cycle arrest and p21WAF1 expression in H1299 cells, but not in Saos-2. This data shows that TAp73 isoforms act differently depending on the tumour cell background, and have important implications for p73-mediated therapeutic responses in individual human cancer patients.

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Proteotoxic Stress Induces a Cell-Cycle Arrest by Stimulating Lon to Degrade the Replication Initiator DnaA

Cell ◽

10.1016/j.cell.2013.06.034 ◽

2013 ◽

Vol 154 (3) ◽

pp. 623-636 ◽

Cited By ~ 103

Author(s):

Kristina Jonas ◽

Jing Liu ◽

Peter Chien ◽

Michael T. Laub

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Proteotoxic Stress ◽

Cycle Arrest ◽

A Cell ◽

Replication Initiator

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Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-07-0217 ◽

2007 ◽

Vol 6 (10) ◽

pp. 2686-2695 ◽

Cited By ~ 78

Author(s):

E.-R. Hahm ◽

S. V. Singh

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Protein Level ◽

Transcriptional Activity ◽

Phase Cell ◽

G1 Phase ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Cycle Arrest

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Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0434312100 ◽

2003 ◽

Vol 100 (5) ◽

pp. 2468-2473 ◽

Cited By ~ 223

Author(s):

J. W. Voncken ◽

B. A. J. Roelen ◽

M. Roefs ◽

S. de Vries ◽

E. Verhoeven ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Inhibition

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p53 Mutation at Serine 249 and Its Gain of Function Are Highly Related to Hepatocellular Carcinoma after Smoking Exposure

Public Health Genomics ◽

10.1159/000516598 ◽

2021 ◽

pp. 1-11

Author(s):

Huai Wang ◽

Lu Chen ◽

Tong Zhou ◽

Zhongwei Zhang ◽

Canwei Zeng

Keyword(s):

Hepatocellular Carcinoma ◽

Transcriptional Activity ◽

Direct Sequencing ◽

Close Correlation ◽

P53 Mutation ◽

Gain Of Function ◽

Reverse Transcription Pcr ◽

Smoking Exposure ◽

Significant Difference ◽

Dose Response Effect

Background: It has been convincingly suggested that a close correlation exists between the incidence of hepatocellular carcinoma (HCC) and cigarette smoking. However, the underlying effect of smoking on HCC is not clear. Methods: A binary unconditional logistic regression was used for the data on a total of 300 cases and 612 controls. The approach of functional analysis of separated alleles in yeast and direct sequencing of TP53 mutations were applied to analyze the p53 status in the HCC group. The relationship between p53 mutation at serine 249 (p53-RS) and smoking was assessed. Quantitative reverse transcription PCR was employed for the evaluation to transcriptional activity of p53 and p53-RS. Results: Smoking was linked to the risk of HCC with an increased dose-response effect. Moreover, among subjects who did not drink, the risks of HCC were significantly increased for smokers between HCC and controls. Besides, there was an increase in the number of HCC in smokers compared to nonsmokers after exclusion of HBV and/or HCV infection. Also, a significant difference was observed in the incidence of p53-RS between smokers and nonsmokers the HCC group. Furthermore, the p53-RS transcriptional activity was significantly increased in tumor tissues. Conclusions: It strongly demonstrated that tobacco smoking is positively and independently associated with HCC, which may be attributed to p53-RS and its gain of function.

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