Studies on the molecular mechanism of mutant p53 mediated chemo-resistance and its related oncogenic gain of functions in human cancer
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Studies on the molecular mechanism of mutant p53 mediated chemo-resistance and its related oncogenic gain of functions in human cancer
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| Creator |
Datta, Arindam
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| Subject |
Cancer Biology and Inflammatory Disorder Division
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| Description |
More than half of the human cancers harbor TP53 mutation. These are mostly missense mutations that confer both loss-of-function and gain-of-function (GOF) properties to the p53 protein. Besides losing wild type tumor suppressor activities, certain tumor associated p53 missense mutants gain novel oncogenic functions and actively drive tumorigenesis by promoting several cancer-inducing mechanisms. “Gain-of-function” mutant p53 physically interacts with other cellular proteins and can also regulate crucial genes and non coding RNAs by acting as an oncogenic transcription factor. Reports suggest that transcriptional property is one of the crucial mechanisms by which mutant p53 confers its gain-of-function activities. Mutant p53 modulates diverse signaling pathways different from those regulated by the wild type protein and promotes cancer phenotypes including increased cellular proliferation, metastasis, invasion and enhanced chemoresistance. Although several studies over the last decade have identified multiple cellular pathways and molecular mechanisms underlying mutant p53 gain-of-functions, many more still need to be explored to completely unravel the growing complexity of oncogenic mutant p53.
In this study, we investigated the role of GOF mutant p53 in regulating DNA replication, a commonly altered pathway in human cancer. We report that Cdc7-dependent increased replication initiation enables mutant p53 to confer oncogenic phenotypes. We found DNA replication as the most significantly altered pathway by GOF mutant p53 in lung adenocarcinoma patients with significant up-regulation of replication initiation factor CDC7 kinase. We showed that mutant p53 cooperates with Myb transcription factor in vivo and transactivates CDC7 in cancer cells. Chromatin enrichment of pre-initiation complex proteins such as phosphorylated Mcm2 and Cdc45 suggested increased replication initiation in mutant p53 cells. Furthermore, DNA fiber assay confirmed Cdc7-mediated increased origin firing in cells expressing mutant p53. Importantly, Cdc7 inhibition significantly abrogated the anchorage-independent growth and chemoresistance phenotypes of mutant p53 expressing cancer cells. We also found significant correlation between CDC7 overexpression and poor survival of the lung adenocarcinoma patients harboring p53 mutation. Thus, our study suggests Cdc7-dependent altered replication initiation as an essential factor in mutant p53 gain-of-functions. We propose that targeting Cdc7 kinase may be an effective strategy in treating human cancers harboring mutant p53
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| Date |
2016-09-26
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2559/1/Arindam_Datta_4594(Sc.)_11.pdf
Datta, Arindam (2016) Studies on the molecular mechanism of mutant p53 mediated chemo-resistance and its related oncogenic gain of functions in human cancer. PhD thesis, CU. |
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| Relation |
http://www.eprints.iicb.res.in/2559/
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