The Circadian Factor Period 2 Modulates P53 Stability And Function In Downstream Signaling

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The human Period 2 (hPer2) factor is a transcriptional regulator placed at the core of the circadian clock mechanism responsible for generating the negative feedback loop that sustains the clock. Its relevance to human diseases is underlined by alterations in its function that impacts many biochemical and physiological processes and, when absent, results in the development of various cancers. The tumor suppressor role of Per2 is speculated to involve transcriptional activation of p53, altered expression of cell cycle components, and regulation of the DNA-damage response pathway. However, it is entirely unclear how Per2 operates mechanistically. First, we identified hPer2 binds the C-terminus half of human p53 (hp53) and forms a stable trimeric complex with hp53’s negative regulator, the oncogenic protein Mdm2. Second, we determined that hPer2 binding to hp53 prevents Mdm2 from ubiquitinating and targeting hp53 by the proteasome. Accordingly, downregulation of hPer2 expression directly impacts hp53 levels whereas its overexpression influences both hp53 protein stability and transcription. Furthermore, we spatially define the distribution of the trimeric complex and determine the site for processing to be located in the nucleus. Third, we establish that hp53-mediated gene transcription is influenced by the presence of hPer2. Target genes such as 14-3-3σ, hp21WAF1/CIP1, and gadd45α show a synergistic increase in expression when hPer2 and hp53 are co-expressed in a hp53-deficient background. This result is the direct consequence of hPer2 dissociation of hp53 as result of checkpoint activation as shown by studies performed using a constitutively bound form of the hPer2/hp53 complex. Overall, our findings directly place hPer2 at the heart of the hp53-mediated response by modulating its stability and controlling its function. Citation Format: Carla V. Finkielstein, Tetsuya Gotoh, Marian Vila-Caballer, carlo santos, jingjing liu, jianhua yang. The circadian factor period 2 modulates p53 stability and function in downstream signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5173. doi:10.1158/1538-7445.AM2013-5173 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.