| Type of Document |
Dissertation |
| Author |
Bansal, Pallavi
|
| Author's Email Address |
pab60@pitt.edu |
| URN |
etd-04262007-133006 |
| Title |
Induction of Cdc25B following DNA damage: Implications for cell cycle resumption and tumorigenesis |
| Degree |
Doctor of Philosophy |
| Program |
Molecular Pharmacology |
| School |
School of Medicine |
| Advisory Committee |
| Advisor Name |
Title |
| Dr. Don DeFranco, Ph.D |
Committee Chair |
| Dr. Baskaran Rajasekaran, Ph.D |
Committee Member |
| Dr. John S. Lazo, Ph.D |
Committee Member |
| Dr. Richard A. Steinman, M.D. Ph.D |
Committee Member |
| Dr. Thomas E. Smithgall, Ph.D |
Committee Member |
|
| Keywords |
- Cell cycle
- BPDE
- Cdc25
- UV
- DNA damage
|
| Date of Defense |
2007-03-19 |
| Availability |
unrestricted |
Abstract
The overall hypothesis of this dissertation was that Cdc25B is an important regulator of the cellular response to DNA damage and defection from the normal response could promote tumorigenesis by enhancing genomic instability. Conventionally, DNA damage is generally thought to inhibit Cdc25 functionality to induce cell cycle arrest. However, recently a crucial role of Cdc25B in the cell cycle resumption after DNA damage was identified. To understand the precise regulation of Cdc25B following DNA damage, I examined the effect of mechanistically distinct DNA damaging agents on Cdc25B. Secondly, experiments were performed to elucidate how Cdc25B participates in the recovery from the checkpoints induced cell cycle arrest. Finally, the mechanism by which Cdc25B contributes to anti-BPDE induced tumorigenesis was investigated. The results of our studies revealed that Cdc25B was rapidly induced following DNA damage and levels of Cdc25B regulated the number of cells existing G2 into mitosis. Increased expression of Cdc25B did not affect the G2/M checkpoint engagement immediately following DNA damage; however, increased Cdc25B reduced the time required for cell cycle resumption. Using UV irradiation as the prototypic damaging agent, the increase in Cdc25B levels was found to be regulated by ATR/Chk1 via post-transcriptional mechanism, potentially by affecting Cdc25B protein stability. Furthermore, Cdc25B was found to be essential for anti-BPDE-induced neoplastic transformation. Additionally, Cdc25B facilitated resumption in the presence of DNA damage following anti-BPDE thus indicating that Cdc25B contributes to tumorigenesis by regulating premature recovery from checkpoints without completion of DNA repair. Finally, increased Cdc25B activated checkpoints in the absence of overt DNA damage suggesting that Cdc25B enables genomic instability by promoting selection of cells with deregulated checkpoint signaling.
To conclude, studies presented in this dissertation identified a novel role of Cdc25B following DNA damage and elucidated the molecular mechanisms by which Cdc25B regulates anti-BPDE induced tumorigenesis.
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BansalP2007.pdf |
3.22 Mb |
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