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

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.

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

2020 ◽  
Author(s):  
Özge Cicek Sener ◽  
Adrian Stender ◽  
Luisa Klemke ◽  
Nadine Stark ◽  
Tamara Isermann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Loss Of Heterozygosity ◽  
Driving Force ◽  
Transcriptional Activity ◽  
Protein Stabilization ◽  
List Type ◽  
Heat Shock Factor 1 ◽  
Gain Of Function ◽  
Proteotoxic Stress ◽  
Cell Cycle Inhibition

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

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

2008 ◽  
Vol 7 (9) ◽  
pp. 1441-1449 ◽  
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

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

Cell ◽  
2013 ◽  
Vol 154 (3) ◽  
pp. 623-636 ◽  
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

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

2003 ◽  
Vol 100 (5) ◽  
pp. 2468-2473 ◽  
Author(s):  
J. W. Voncken ◽  
B. A. J. Roelen ◽  
M. Roefs ◽  
S. de Vries ◽  
E. Verhoeven ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Inhibition

scholarly journals Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs

2010 ◽  
Vol 67 (5) ◽  
pp. 1157-1166 ◽  
Author(s):  
Anja Frömberg ◽  
Daniela Gutsch ◽  
Daniel Schulze ◽  
Claudia Vollbracht ◽  
Gabriele Weiss ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Cells ◽  
Cytostatic Drugs ◽  
Cell Cycle Inhibition

Abstract 2357: Src Kinase Inhibition Blocks Thrombin-induced Brain Injuries without Cognitive Side Effects

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Da-Zhi Liu ◽  
Bradley P Ander ◽  
Ali Izadi ◽  
Ken Van ◽  
Xinhua Zhan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cognitive Deficits ◽  
Neuronal Cell ◽  
Thrombin Injection ◽  
Cell Cycle Reentry ◽  
Cell Cycle Inhibition ◽  
Mature Neurons ◽  
Cognitive Side Effects

Intracerebral hemorrhage (ICH) activates thrombin, a potent mitogen. Thrombin triggers mitosis by modulating several intracellular mitogenic molecules including Src family kinases. These molecules regulate mitogen-activated protein kinases (MAPKs) and cell cycle proteins such as cyclin-dependent kinases (Cdks); and play critical roles in mitogenic signaling pathways and cell cycle progression. Since aberrant cell cycle reentry results in death of mature neurons, cell cycle inhibition appears to be a candidate strategy for the treatment of neurological diseases including ICH. However, this can also block cell cycle (proliferation) of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits. We hypothesized that inhibition of cell cycle by blocking mitogenic signaling molecules (i.e., Src family kinase members) blocks cell cycle reentry of mature neurons without injuring NPCs, which will avoid cognitive side effects during cell cycle inhibition treatment for ICH. Our data shows: (1) Thrombin 30U/ml results in apoptosis of mature neurons via neuronal cell cycle reentry in vitro ; (2) PP2 (Src family kinase inhibitor) 0.3 µM attenuates the thrombin-induced neuronal apoptosis via blocking neuronal cell cycle reentry, but does not affect the viability of NPCs at the same doses in vitro ; (3) Intracerebral ventricular thrombin injection (20U, i.c.v.) results in neuron loss in hippocampus and cognitive deficits 5 weeks after thrombin injection in vivo ; (4) PP2 (1mg/kg, i.p.), given immediately after thrombin injection (i.c.v.), blocks the thrombin-induced neuron loss in hippocampus and cognitive deficits, whereas PP2 on its own at the same doses does not affect normal cognition in vivo . These suggest that Src kinase inhibition prevents hippocampal neuron death via blocking neuronal cell cycle reentry after ICH, but does not affect survival of NPCs.

scholarly journals Arginine deprivation in KB cells: I. Effect on cell cycle progress

1977 ◽  
Vol 75 (3) ◽  
pp. 881-888 ◽  
Author(s):  
AS Weissfeld ◽  
H Rouse
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Tritiated Thymidine ◽  
Experimental Period ◽  
Cell Multiplication ◽  
Starvation Period ◽  
Kb Cells ◽  
Insoluble Material ◽  
Cell Cycle Inhibition ◽  
Cellular Dna

When exponentially growing KB cells were deprived of arginine, cell multiplication ceased after 12 h but viability was maintained throughout the experimental period (42-48 h). Although tritiated thymidine ([(3)H]TdR) incorporation into acid-insoluble material declined to 5 percent of the initial rate, the fraction of cells engaged in DNA synthesis, determined by autoradiography, remained constant throughout the starvation period and approximately equal to the synthesizing fraction in exponentially growing controls (40 percent). Continous [(3)H]TdR-labeling indicated that 80 percent of the arginine-starved cells incorporated (3)H at some time during a 48-h deprivation period. Thus, some cells ceased DNA synthesis, whereas some initially nonsynthesizing cells initiated DNA synthesis during starvation. Flow microfluorometric profiles of distribution of cellular DNA contents at the end of the starvation period indicated that essentially no cells had a 4c or G2 complement. If arginine was restored after 30 h of starvation, cultures resumed active, largely asynchronous division after a 16-h lag. Autoradiographs of metaphase figures from cultures continuously labeled with [(3)H]TdR after restoration indicated that all cells in the culture underwent DNA synthesis before dividing. It was concluded that the majority of cells in arginine-starved cultures are arrested in neither a normal G1 nor G2. It is proposed that for an exponential culture, i.e. from most positions in the cell cycle, inhibition of cell growth after arginine with withdrawal centers on the ability of cells to complete replication of their DNA.

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