Tumor development is a multi-step process that depends upon the successive activation of oncogenes and inactivation of tumor suppressor genes. p53 is mutated in about 50% of human tumors and the p53 protein is known as a """"""""guardian of the genome"""""""" because of its crucial role in coordinating cellular responses to varies types of stress. The tumor suppression effects of p53 are mediated by a number of mechanisms including cell cycle arrest, apoptosis, and senescence. The principal functions of p53 acts through its activity as a DNA-binding transcription factor. The importance of its transcriptional activity is underscored by the fact that most tumor-associated p53 mutations occur within its central core domain responsible for sequence-specific DNA binding. p53 is tightly regulated, such that its protein product usually exists in a latent form, and at low levels, in unstressed cells. Upon various types of stress, the steady-state levels and transcriptional activity of p53 increase dramatically. Nevertheless, it is becoming more apparent that the mechanisms that govern the transcriptional program of p53 are not as simple as once thought. In our early studies, we found that histone acetyltransferase CBP/p300 promotes p53-dependent transcription by directly acetylating lysine residues in the C-terminal region of p53. This study led to the notion that acetylation is a general protein modification for the regulation of non-histone proteins. Recently, we have identified additional modification sites by CBP/p300. We found that modification of lysine 164 (K164) by CBP/p300 is critical for p21 activation as well as p53-mediated tumor suppression function. Moreover, p53 is down-regulated by deacetylase complexes such as Sirt1 and HDAC1 through deacetylation. In summary, for the past several years, our lab has made significant contributions to understand this dynamic pathway of p53 regulation. However, our new findings also raise more general questions regarding the roles and mechanisms of p53 in suppressing tumor progression. For example, 1) how does p53 activate its numerous targets specifically and what is the molecular basis of p53 acetylation in functional regulation? 2) How important is p53 deacetylation in modulating p53-mediated function in vivo? The central hypothesis to be tested here is that p53 requires multiple layers of regulatory control to ensure temporal and spatial functions and that site specific acetylation of p53 plays a major part in the scope of controlling p53 function through activating p53 responsive targets in a promoter-specific manner. To accomplish these goals, the following two specific aims are proposed.
In Aim1, we will define the role of p53 acetylation in modulating its transcriptional activation program in a promoter-specific manner during stress responses. We will use both biochemical and molecular biological approaches, to identify the major acetylation sites on p53 and investigate the functional consequence of these modifications in tumor suppression.
In Aim 2, we will elucidate the regulatory role of p53 deacetylation in modulating its mediated tumor suppressor function. By using both cell biology and genetics approaches, we will examine the effect of p53 acetylation levels in modulating tumor suppression function in vivo.
The p53 tumor suppressor is mutated in every type of human cancers. p53-mediated transcriptional activation is essential for its ability in suppressing tumor formation. This study will elucidate the molecular mechanisms for p53 activation in tumor suppression and yield crucial insights regarding how to target this pathway in cancer therapy.
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