Ducruet, Alexander Pelletier
(2004)
REGULATION OF CDC25A IN HUMAN TUMOR CELLS BY CYCLIN-DEPENDENT KINASE 2.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Deregulation of normal cell cycle control is essential for malignant transformation. The Cdc25A dual-specificity phosphatase promotes cell cycle progression by dephosphorylating and activating the cyclin-dependent kinases. Cdc25A has oncogenic and anti-apoptotic activity and is overexpressed in many human tumors. The mechanisms by which Cdc25A is overexpressed in human cancer are unknown. Cdc25A protein levels are downregulated by cell cycle checkpoints in response to genotoxic stress; cell cycle checkpoints are frequently compromised in tumor cells. In addition, under normal physiologic conditions, the half-life of Cdc25A protein is short. Alterations to physiologic Cdc25A regulatory mechanisms could be sufficient to result in oncogenic overexpression of this cell cycle regulatory protein. While Cdc25A downregulation in response to genotoxic stress occurs through defined signal transduction pathways, regulation of Cdc25A protein levels in non-stressed cells is poorly understood. The purpose of this thesis was to examine the physiological regulation of Cdc25A protein levels in human tumor cells. The goals of our studies were: 1) to investigate regulatory mechanisms of Cdc25A protein levels in non-stressed human tumor cells; 2) to understand how Cdk2 kinase activity regulates Cdc25A protein levels; and 3) to explore the mechanism by which Cdk2 kinase activity regulates Cdc25A protein turnover. The results of our studies revealed that Cdc25A protein half-life in non-stressed interphase cells is regulated, in part, by Cdk2 kinase activity, and that Cdk2 does not regulate Cdc25A turnover by affecting several known signal transduction pathways that control Cdc25A protein stability. Recent reports on the role of ubiquitin ligases in physiologic Cdc25A turnover have identified several phosphorylation sites that are necessary for efficient Cdc25A recruitment to ubiquitin ligases. The kinase(s) responsible for phosphorylating these serine residues remain to be identified, although Cdk2 could be one prime candidate. While initial reports of the interactions between Cdc25A and Cdk2 focused on an auto-amplification feedback loop that results in increased catalytic activity of both proteins, it now appears that Cdk2 also regulates Cdc25A stability and plays an important role in regulating Cdc25A protein levels during interphase progression.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Ducruet, Alexander Pelletier | apdst11@pitt.edu | APDST11 | |
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| ETD Committee: |
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| Date: |
13 April 2004 |
| Date Type: |
Completion |
| Defense Date: |
25 March 2004 |
| Approval Date: |
13 April 2004 |
| Submission Date: |
13 April 2004 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Cdc25A; Cell cycle; Cyclin-dependent kinase 2; Dominant-negative mutant; Roscovitine |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04132004-084338/, etd-04132004-084338 |
| Date Deposited: |
10 Nov 2011 19:36 |
| Last Modified: |
15 Nov 2016 13:39 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/7084 |
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