My overall training goal is through the F99 predoctoral and K00 postdoctoral training to prepare me to become a productive independent scientist in cancer research field. To achieve this goal, I will 1) continue to study the role of mutp53 interacting protein, Rac1, in promoting mutp53 GOF in tumorigenesis during the F99 phase; and 2) study mechanism of cancer metastasis, in particular, the crosstalk between cancer cells and microenvironment which leads to metastasis of tumors, especially those carrying mutp53 during the K00 phase. p53 is one of the most frequently mutated genes in human cancer. Besides the loss of tumor-suppressive activity of wild type p53, many tumor-associated mutant p53 (mutp53) proteins gain oncogenic functions to promote tumorigenesis, defined as gain of function (GOF). Mutp53 often accumulates to high levels in tumors, which is critical for mutp53 to exert GOF. Destabilizing mutp53 to inhibit mutp53 GOF in tumorigenesis is an attractive novel strategy to target cancer carrying mutp53. The goal of this proposed research is to study the mechanisms for mutp53 accumulation and GOF, which are poorly understood. I have searched for candidate proteins that regulate mutp53 protein levels and/or GOF by using an unbiased high throughput screening: immunoprecipitation combined with mass spectrometry screening. Through this approach, I identified several novel mutp53 binding proteins that regulate mutp53 protein levels and/or function, including co-chaperone proteins BAG2 and BAG5 and an AAA+ ATPase Pontin. My focus for the F99 phase is on a novel mutp53 binding partner, Rac1. Rac1 is a small GTPase that plays an important role in multiple cellular processes, including cell proliferation and survival. The proposed study is to test the hypothesis that mutp53 GOF is in part through its interaction with Rac1 to activate Rac1, which in turn promotes tumor growth. I anticipate that this study will greatly increase our understanding of the mechanisms underlying mutp53 GOF in tumorigenesis. Results from this study will i) provide direct evidence that Rac1 activation by mutp53 is an important mechanism for mutp53 GOF in tumorigenesis, and ii) the rationale for blocking Rac1 as a novel therapeutic strategy for tumors containing mutp53. For the K00 phase, the research direction I would like to pursue is to study the mechanisms of cancer metastasis, in particular, the role and mechanism of tumor microenvironment (TME) in cancer metastasis. I plan to investigate the crosstalk between cancer cells and TME to understand 1) how cancers change and regulate TME; 2) how TME regulates cancer metastasis; 3) the role of p53 (both wild type and mutant p53) in the crosstalk between cancer cells and TME and its contribution to cancer metastasis. The goal is to increase the understanding on the mechanisms underlying metastasis with the hope to develop new strategies to prevent cancer metastasis.
My overall training goal is through the F99 predoctoral and K00 postdoctoral training to prepare me to become a productive independent scientist in cancer research field. To achieve this goal, during F99 phase, I will study the role of mutp53 interacting protein, Rac1, in promoting mutp53 GOF in tumorigenesis; and during K00 phase, I plan to study mechanism of cancer metastasis, in particular the crosstalk between tumor cells and tissue/tumor microenvironment which leads to increased metastasis, especially those tumors carrying mutp53. Results from this study will increase our understanding of mechanism underlying mutp53 protein accumulation and GOF, which can be developed for cancer therapy.
| Zhao, Yuhan; Wu, Lihua; Yue, Xuetian et al. (2018) A polymorphism in the tumor suppressor p53 affects aging and longevity in mouse models. Elife 7: |
| Yue, Xuetian; Zhang, Cen; Zhao, Yuhan et al. (2017) Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression. Genes Dev 31:1641-1654 |
