The p53/p73 - p21(CIP1) tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells.
View Publication On PubMed
Export 
BiBTeXWhole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21(CIP1), represents a critical target gene of p53/p73. Loss of p21(CIP1) unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21(CIP1) tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.
SEEK ID: https://seek-for2800.de/publications/3
PubMed ID: 33168930
Projects: SP-2: Molecular mechanisms of replication stress-induced mitotic chromos...
Publication type: Journal
Journal: Oncogene
Citation: Oncogene. 2021 Jan;40(2):436-451. doi: 10.1038/s41388-020-01524-4. Epub 2020 Nov 9.
Date Published: 11th Nov 2020
Registered Mode: by PubMed ID
Export PNG
Download
Submitter
Views: 846
Created: 12th Jan 2022 at 06:58
Last updated: 14th Mar 2023 at 14:55
TagsThis item has not yet been tagged.
AttributionsNone
Related items
Projects: Test, SP-3: A statistical modeling approach to identify common triggers for replication stress and mitotic chromosome missegregation, SP-1: Deciphering signaling pathways that promote accurate chromosome segregation after replication stress, SP-2: Molecular mechanisms of replication stress-induced mitotic chromosome missegregation, SP9: Mutual impact of replication origin firing regulation and mitotic chromosome segregation
Institutions: University of Applied Sciences Koblenz, Institute of Molecular Biology, University of Göttingen University Medical Center (UMG) Institute of Molecular Oncology, Section for Cellular Oncology, University of Duisburg-Essen
https://orcid.org/0000-0003-3977-9982
Our Research Unit addresses an important question on the origin of chromosome instability (CIN), which causes structural as well as numerical chromosome aberrations. Importantly, CIN and increased levels of chromosome aberrations are closely associated with many human diseases including cancer, neurodegenerative diseases and age-related syndromes and can act as key drivers for disease development and progression. An important condition that causes structural chromosome instability (S-CIN) leading ...
Projects: SP-3: A statistical modeling approach to identify common triggers for replication stress and mitotic chromosome missegregation, SP-1: Deciphering signaling pathways that promote accurate chromosome segregation after replication stress, SP-2: Molecular mechanisms of replication stress-induced mitotic chromosome missegregation, SP-4: Centrosome integrity as a determinant of replication stress and mitotic dysfunction, SP-5: Impaired chromosome integrity caused by mutations in members of the BTR complex, SP-6: Proteomics of mitotic inter sister chromatid junctions, SP-8: The causes of replication stress in response to whole chromosomal aneuploidy, SP-Z: NGS-based approaches for systematic analysis of genomic and chromosome instability Bernd Wollnik, Göttingen, SP9: Mutual impact of replication origin firing regulation and mitotic chromosome segregation
Web page: https://for2800.de/
Structural and numerical chromosome aberrations are commonly and concomitantly detected in cancer and in age-related syndrome cells suggesting a functional relationship between structural and whole chromosome instability (S-CIN and W-CIN, respectively). Recent evidence suggests that replication stress can not only drive S-CIN and the generation of structural chromosome aberrations, but might also be involved in W-CIN leading to whole chromosome missegregation during mitosis resulting in aneuploidy. ...
Programme: FOR2800
Public web page: https://for2800.de/cases/sub-project-2-molecular-mechanisms-of-replication-stress-induced-mitotic-chromosome-missegregation/
Start date: 1st Jan 2019
Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes and W-CIN. CDKN1A, ...
