Robert Wood Johnson Medical School
Dept. of Radiation Oncology
The Cancer Institute of New Jersey
195 Little Albany Street
New Brunswick, NJ 08903-2681
p53; tumor suppressor; stress response; apoptosis; single nucleotide polymorphism; microRNA; tumor; development and reproduction
1. Our lab is interested in understanding of the regulation of p53 and its signaling pathway.
As "the guardian of the genome", the p53 tumor suppressor gene plays a critical role in maintaining genomic stability and tumor prevention. p53 is the most frequently-mutated gene in human tumors; over 50% of all tumors harbor mutations in the p53 gene, and over 80% of tumors have a dysfunctional p53 signaling pathway. The p53 protein responds to a wide variety of stress signals. As a transcription factor, once p53 is activated it selectively transcribes a set of target genes to initiate various cellular responses to prevent the propagation of cells that could potentially become cancerous.
In particular, we are interested in the connection among chronic psychological stress, p53 function and tumorigenesis. For cancer patients, both diagnosis and treatment are stressful events. Our research suggests that chronic stress attenuates p53 function, which provides the foundation for future studies on stress level monitoring and p53 activation as an important potential intervention strategy for cancer patients.
Mutant p53 (mutp53) proteins often accumulate to high levels in cancers and gain oncogenic functions (gain-of-function, GOF) to promote tumorigenesis. Following work from my lab contributes to the understanding of mechanism of mutp53 accumulation and GOF in tumorigenesis: a) we identified two novel mechanisms for mutp53 accumulation in tumor cells: i) the overexpression of BAG2 in tumors interacts with mutp53 protein which inhibits MDM2 to bind to and degrade mutp53; ii) the overexpression of tumor-associated MDM2 isoforms in tumors interacts with full length MDM2 to inhibit MDM2-mediated mutp53 degradation; b) we identified a novel mutp53 binding partner, Pontin, that plays an important role in promoting mutp53 GOF through regulating the transcriptional activity of mutp53.
2. I identified an important p53 function in addition to tumor suppression; p53 plays a critical role in embryonic implantation and maternal reproduction through the regulation of a novel p53 target, LIF, in mice and humans. This set of work for the first time demonstrates the important physiological role of p53 and its pathway in reproduction in vertebrates.
3. Another line of research in our lab on LIF is to investigate its role in tumorigenesis, which is under studied. We found that a) LIF is an important negative regulator of p53 in human tumors; b) LIF activates the AKT-mTOR signaling in tumors, both of which may contribute to the oncogenic function of LIF. c) LIF plays an important role in promoting EMT, tumor metastasis, and the induction of specific microRNA by LIF is an important mechanism. Furthermore, we found that d) hypoxia can induce the LIF expression levels, which could be an important mechanism for the frequent overexpression of LIF in human tumors.