The p53-p21-Cyclin E Pathway in Centrosome Amplification and Chromosome Instability

The p53-p21-Cyclin E Pathway in Centrosome Amplification and Chromosome Instability

Bibliographic Details
Main Author: BENNETT, RICHARD A.
Language:English
Published: University of Cincinnati / OhioLINK 2007
Subjects:
Centrosome
Chromosome Instability
p53
p21
Cyclin E
Cancer
Centrosome amplification
Mitosis
Anticancer drugs
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1189188730
id ndltd-OhioLink-oai-etd.ohiolink.edu-ucin1189188730
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Centrosome
Chromosome Instability
p53
p21
Cyclin E
Cancer
Centrosome amplification
Mitosis
Anticancer drugs
spellingShingle Centrosome
Chromosome Instability
p53
p21
Cyclin E
Cancer
Centrosome amplification
Mitosis
Anticancer drugs
BENNETT, RICHARD A.
The p53-p21-Cyclin E Pathway in Centrosome Amplification and Chromosome Instability
author BENNETT, RICHARD A.
author_facet BENNETT, RICHARD A.
author_sort BENNETT, RICHARD A.
title The p53-p21-Cyclin E Pathway in Centrosome Amplification and Chromosome Instability
title_short The p53-p21-Cyclin E Pathway in Centrosome Amplification and Chromosome Instability
title_full The p53-p21-Cyclin E Pathway in Centrosome Amplification and Chromosome Instability
title_fullStr The p53-p21-Cyclin E Pathway in Centrosome Amplification and Chromosome Instability
title_full_unstemmed The p53-p21-Cyclin E Pathway in Centrosome Amplification and Chromosome Instability
title_sort p53-p21-cyclin e pathway in centrosome amplification and chromosome instability
publisher University of Cincinnati / OhioLINK
publishDate 2007
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1189188730
work_keys_str_mv AT bennettricharda thep53p21cyclinepathwayincentrosomeamplificationandchromosomeinstability
AT bennettricharda p53p21cyclinepathwayincentrosomeamplificationandchromosomeinstability
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin11891887302021-08-03T06:12:09Z The p53-p21-Cyclin E Pathway in Centrosome Amplification and Chromosome Instability BENNETT, RICHARD A. Centrosome Chromosome Instability p53 p21 Cyclin E Cancer Centrosome amplification Mitosis Anticancer drugs Cancer is characterized by cells that have many genetic mutations. Chromosome instability is a hallmark of cancer, because it promotes the acquisition of the many mutations necessary for malignancy. Centrosome amplification is a major factor in chromosome instability because it leads to multipolar spindles, which directs the unequal segregation of chromosomes during mitosis. Centrosome amplification occurs when the mechanisms that regulate centrosome duplication are disrupted. Although the mechanisms that regulate centrosome duplication are not clear, it is known that the p53-p21-cyclin E pathway plays a major role in regulating centrosome duplication. p53, a tumor suppressor, induces the expression of p21, a cell cycle inhibitor, which inhibits the activity of cdk2/cyclin E. Previous work has shown that disruption of this pathway (loss of p53 or p21, or overexpression of cyclin E) can induce centrosome amplification. In this work, we study various aspects of this pathway and its effect on centrosome duplication. We show that common anti-cancer drugs that inhibit S phase uncouple centrosome duplication and DNA synthesis, leading to an increase in centrosome amplification and chromosome instability. This may help to explain why recurrent tumors are more malignant than their primary counterpart is. If some cells receive low doses of these drugs, it is possible that they can reversibly arrest in S phase, but allow centrosomes to duplicate. Once the drugs are gone, cells can re-enter the cell cycle with amplified centrosomes. As a result, chromosome instability occurs and cells can invade and destroy nearby tissues and spread to other parts of the body. p53 probably controls centrosome duplication via multiple pathways. To examine further the role of the p53-p21-cyclin E pathway in drug-induced centrosome amplification, we show that cyclin E is required for centrosome amplification to occur in drug-treated cells. Cells lacking cyclin E show minimal centrosome amplification compared to cells that express cyclin E. These data indicate that treatment of p53-null cells probably exploits the inactive p53-p21-cyclin E pathway to induce centrosome amplification. Fibroblasts from cyclin E-knockout mice are viable and centrosome duplication occurs normally, thus questioning the necessity of cyclin E in regulating centrosome duplication. Since cyclin A is also a binding partner of cdk2, we show that cyclin A may substitute for the loss of cyclin E in regulating centrosome duplication. Expression of wild-type cyclin A in fibroblasts lacking cyclin E induces centrosome amplification, but not at the same level as exogenous wild-type cyclin E, indicating that cyclin E is the preferred binding partner of cdk2 in terms of centrosome duplication regulation. We also directly investigated the role p53 centrosome localization plays in centrosome duplication regulation. p53 is known to localize to centrosomes, but its functional significance is unknown. Using a p53 mutant that is unable to leave the nucleus, we show that both the transcriptional activity and the centrosome localization of p53 are required for p53 to fully regulate centrosome duplication, indicating that it may have non-transcriptional activities that regulate centrosome duplication. Lastly, p21 regulates centrosome duplication by inhibiting cdk2/cyclin E activity. However, p21 also binds and inhibits proliferating cell nuclear antigen (PCNA), but the effect on centrosome duplication is unknown. Therefore, we further evaluated the relative contribution of both binding regions of p21 (CDK and PCNA) in regulating centrosome duplication. We show that p21 regulates centrosome duplication through its ability to bind and inhibit cdk2/cyclin E, rather than PCNA. 2007 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1189188730 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1189188730 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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