The goal of the planned research is to elucidate how the p53 tumor suppressor elicits apoptosis in tumor cells. Under some conditions, induction of p53 leads to its transactivation of a set of pro-apoptotic target genes. Nevertheless, a transcription-independent role for p53 in causing apoptosis has been documented. It is planned to examine both the transcription-dependent and -independent roles of p53 in apoptosis in three specific aims. First, we discovered that mutation of H115 in the L1 loop of the p53 core domain produces p53 protein that is more effective than wild-type p53 in DNA binding, transactivation and cell cycle arrest and yet is impaired in apoptosis. We will examine the properties of H115N and other p53 variants mutated in the L1 loop region. The transcriptional program of L1 loop mutants and their effects in cells and in mice will be evaluated. Second, we will continue to explore in depth the apoptotic features of cells expressing a transcriptionally impaired mutant p53 (P53Q22/S23) in order to learn about the different pathways to cell death that p53 can bring about. Third, we will use a biochemical and proteomics approach to discover unique features of promoters of apoptotic gene targets with which p53 associates.
| Laptenko, Oleg; Shiff, Idit; Freed-Pastor, Will et al. (2015) The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain. Mol Cell 57:1034-1046 |
| Rokudai, Susumu; Laptenko, Oleg; Arnal, Suzzette M et al. (2013) MOZ increases p53 acetylation and premature senescence through its complex formation with PML. Proc Natl Acad Sci U S A 110:3895-900 |
| Laptenko, Oleg; Prives, Carol (2013) Anything but simple: a phosphorylation-driven toggle within Brd4 triggers gene-specific transcriptional activation. Mol Cell 49:838-9 |
| Laptenko, Oleg; Prives, Carol (2012) The p53-HAT connection: PCAF rules? Cell Cycle 11:2975-6 |
| Barsotti, Anthony M; Beckerman, Rachel; Laptenko, Oleg et al. (2012) p53-Dependent induction of PVT1 and miR-1204. J Biol Chem 287:2509-19 |
| Freed-Pastor, William A; Mizuno, Hideaki; Zhao, Xi et al. (2012) Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148:244-58 |
| Freed-Pastor, William A; Prives, Carol (2012) Mutant p53: one name, many proteins. Genes Dev 26:1268-86 |
| Singer, Stephan; Zhao, Ruiying; Barsotti, Anthony M et al. (2012) Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes. Mol Cell 48:799-810 |
| Laptenko, Oleg; Beckerman, Rachel; Freulich, Ella et al. (2011) p53 binding to nucleosomes within the p21 promoter in vivo leads to nucleosome loss and transcriptional activation. Proc Natl Acad Sci U S A 108:10385-90 |
| Beckerman, Rachel; Prives, Carol (2010) Transcriptional regulation by p53. Cold Spring Harb Perspect Biol 2:a000935 |
Showing the most recent 10 out of 22 publications
