Mechanism of p53-dependent tumor suppression Summary P53 tumor suppressor is activated in response to stress signals, including DNA damage and hypoxia. Upon activation, p53 induces a plethora of pro-survival and pro-apoptotic genes as well as the ones that in turn modulate p53 expression and activity. Among these is p21, a cyclin-dependent kinase inhibitor that mediates p53 to induce cell cycle arrest. Previously, we found that RNPC1, also called Rbm38 and a RNA- binding protein, is transcriptionally regulated by DNA damage in a p53-dependent manner. Interestingly, we found that RNPC1 directly binds to p21 transcript and enhances p21 mRNA stability. In addition, RNPC1 binds to p53 transcript and suppresses p53 mRNA translation. Thus, we identified p53-RNPC1 as a novel feedback loop in the p53 pathway. The significance of the loop is exemplified by our recent observations: (1) RNPC1 may play a central role in transmitting signals from Akt-GSK3 kinases and Wip1 -/- protein phosphatase to the p53 pathway and (2) RNPC1 MEFs are prone to premature senescence in a p53- -/- dependent manner and RNPC1 mice are prone to premature aging. These observations prompt us to hypothesize that the p53-RNPC loop plays a key role in p53-mediated tumor suppression and longevity, which represents the central hypothesis to be tested in this renewal application. To test this, the following specific aims are proposed:
Aim 1 to determine whether Rbm24, a member of the RNPC family, plays a role in the p53 pathway;
Aim 2 to determine how phosphorylation modulates RNPC1 to regulate p53 mRNA translation;
and Aim 3 to determine whether RNPC1 plays a role in tumor suppression and premature aging in a p53-dependent manner.
Mechanism of P53-Dependent Tumor Suppression Public Health Relevance Statement Due to loss of p53 and other factors that are required for p21 expression, tumor cells are dysfunctional in the cell cycle control. Thus, restoration of proper cel cycle control in tumor cells is an active approach to suppress cell transformation and tumorigenesis. Recently, we showed that p21 mRNA stability is regulated by RNPC1 under both normal and stress conditions. Here, we propose to further analyze how Rbm24 alone and in combination with RNPC1 regulates p21 mRNA stability. Thus, our study may provide an insight into how p21 expression is explored to restore cell cycle control in tumor cells. P53 is known to be activated by post-translational modifications, such as phosphorylation and acetylation. Increasing evidence indicate that other mechanisms play a major role in modulating p53 activity. As a RNA binding protein and a target of p53, we found that RNPC1 binds to p53 transcript and inhibits p53 mRNA translation. Interestingly, RNPC1 locus is found to be altered in cancer. In addition, RNPC1 is found to be highly expressed in breast cancer patients with poor prognosis. Recently, we showed that in dog lymphoma, overexpression of RNPC1 is correlated with decreased expression of p53. Since regulation of p53 activity through its modifiers is a feasible approach to activate p53 in tumor cells, understanding how RNPC1 regulates p53 expression would open a new avenue to activate p53 for cancer therapy. Indeed, upon validation of Akt kinase and Wip1 phosphatase as a modulator of RNPC1 phosphorylation, our study will reveal a novel link among Akt, Wip1, and p53. Considering that Akt inhibitors are used in phase 1-2 clinical trials in patients with solid tumors, the RNPC1-Akt pathway may be used to improve the current class of Akt inhibitors and/or to identify new Akt inhibitors. It is well-established that humans and mice deficient in p53 are prone to tumor formation. In contrast, mutant mice with increased p53 activity are prone to premature aging. Here, we showed that RNPC1-null MEFs are prone to premature senescence in a p53-dependent manner. In addition, we showed that mice deficient in RNPC1 are viable and tumor-free but prone to premature aging. Based on this, RNPC1 is likely to be an ideal molecule to fine-tune the level of p53 to determine p53-dependent tumor suppression and premature aging. Furthermore, considering that RNPC1 is altered in many types of tumors, it may be explored as a target and a marker for extending longevity and for managing cancer.
|Yang, Hee Jung; Zhang, Jin; Yan, Wensheng et al. (2017) Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner. Proc Natl Acad Sci U S A 114:11500-11505|
|Zhang, Yanhong; Qian, Yingjuan; Zhang, Jin et al. (2017) Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. Genes Dev :|
|Lucchesi, Chris; Zhang, Jin; Chen, Xinbin (2016) Modulation of the p53 family network by RNA-binding proteins. Transl Cancer Res 5:676-684|
|Zhang, Jin; Lucchesi, Christopher; Chen, Xinbin (2016) A new function for p53 tetramerization domain in cell fate control. Cell Cycle 15:2854-2855|
|Yan, Wensheng; Scoumanne, Ariane; Jung, Yong-Sam et al. (2016) Mice deficient in poly(C)-binding protein 4 are susceptible to spontaneous tumors through increased expression of ZFP871 that targets p53 for degradation. Genes Dev 30:522-34|
|Zhang, Min; Zhang, Jin; Yan, Wensheng et al. (2016) p73 expression is regulated by ribosomal protein RPL26 through mRNA translation and protein stability. Oncotarget 7:78255-78268|
|Zhang, M; Xu, E; Zhang, J et al. (2015) PPM1D phosphatase, a target of p53 and RBM38 RNA-binding protein, inhibits p53 mRNA translation via dephosphorylation of RBM38. Oncogene 34:5900-11|
|Cho, Seong-Jun; Teng, I-Fang; Zhang, Min et al. (2015) Hypoxia-inducible factor 1 alpha is regulated by RBM38, a RNA-binding protein and a p53 family target, via mRNA translation. Oncotarget 6:305-16|
|Zhang, Yanhong; Young, Ashley; Zhang, Jin et al. (2015) P73 tumor suppressor and its targets, p21 and PUMA, are required for madin-darby canine kidney cell morphogenesis by maintaining an appropriate level of epithelial to mesenchymal transition. Oncotarget 6:13994-4004|
|Cao, Ruibing; Zhang, Jin; Zhang, Min et al. (2015) PPM1D regulates p21 expression via dephoshporylation at serine 123. Cell Cycle 14:641-7|
Showing the most recent 10 out of 46 publications