| dc.identifier.uri | http://hdl.handle.net/11401/77605 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Tumor suppressor protein p53 responds to cellular stress by activating transcriptional and transcription-independent programs that induce apoptosis, growth arrest or senescence. Given its critical tumor suppressing role, p53 is often mutated in human cancers. Once altered by missense mutations in the DNA-binding domain, mutant p53 (mutp53) protein becomes highly stabilized in tumors, which is critical for mutp53′s oncogenic gain-of function. Current insight into the mechanism of tumor-specific stabilization of mutp53 is fragmentary and largely derived from ectopically constructed cell systems. We find that in human cancer cells endogenous mutp53, despite its ability to interact with MDM2, suffers from a profound lack of ubiquitination as the root of its degradation defect. In contrast to wtp53, mutp53 proteins are conformationally aberrant and form a complex with the Heat shock protein 90 (HSP90) chaperone machinery to prevent its degradation. We show that this interaction inhibits MDM2 and CHIP mediated degradation of mutp53. Interference with HSP90 activity by HSP90 siRNA, HSP90 inhibitor 17AAG or histone deacetylase inhibitor SAHA liberates mutp53 from the inhibitory complex and reactivates endogenous MDM2 and CHIP to degrade mutp53. We also show that SAHA and 17AAG exhibit preferential cytotoxicity for mutant compared to wild-type and null p53 human cancer cells. Loss/gain-of-function experiments revealed that although able to exert multiple cellular effects, the cytotoxicity caused by the drugs is mainly due to their ability to degrade mutp53. Thus, our data identifies 17AAG and SAHA as potential candidates for treatment of mutp53 cancers. Through studying the stabilizing effects of heat shock proteins on mutp53, we discovered a novel gain of function activity of mutp53, whereby mutp53 provides superior tolerance to proteotoxic stress in cancer cells. We found mutp53 induces stabilization and phosphoactivation of Heat Shock Factor 1 (HSF1). HSF1 is a heat shock transcription factor that acts as a master regulator of the heat shock response. Moreover, mutp53 protein, via direct interaction with activated p-Ser326 HSF1, facilitates HSF1 recruitment to its specific DNA-binding elements and stimulates transcription of heat-shock proteins, including HSP90. In turn, induced HSP90 stabilizes its oncogenic clients including EGFR, ErbB2 and mutp53, thereby further reinforcing oncogenic signaling. Thus, mutp53 initiates a feed forward loop that renders cancer cells more resistant to adverse conditions, providing a strong survival advantage. | |
| dcterms.available | 2017-09-20T16:52:58Z | |
| dcterms.contributor | Shroyer, Kenneth R | en_US |
| dcterms.contributor | Moll, Ute M | en_US |
| dcterms.contributor | Zong, Wei-Xing | en_US |
| dcterms.contributor | Ju, Jingfang | en_US |
| dcterms.contributor | Lin, Richard Z. | en_US |
| dcterms.creator | Li, Dun | |
| dcterms.dateAccepted | 2017-09-20T16:52:58Z | |
| dcterms.dateSubmitted | 2017-09-20T16:52:58Z | |
| dcterms.description | Department of Genetics | en_US |
| dcterms.extent | 110 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/77605 | |
| dcterms.issued | 2014-12-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:52:58Z (GMT). No. of bitstreams: 1
Li_grad.sunysb_0771E_12070.pdf: 3389706 bytes, checksum: a132c6a734859fcd456c73954206bfb0 (MD5)
Previous issue date: 1 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Cancer, heat shock proteins, HSF1, HSP90, Mutant p53, p53 | |
| dcterms.subject | Biology -- Oncology | |
| dcterms.title | Pharmacological Targeting of Mutant p53 - HSF1 Feed Forward Circuit | |
| dcterms.type | Dissertation | |
