Abstract PL01-02: The two faces of p53: Tumor suppressor and oncogene

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The p53 protein is a sequence-specific transcriptional regulator of multiple genes that control processes associated with tumor suppression such as cell cycle arrest, cell death, senescence, and metabolic homeostasis. It is held in check by two closely related proteins, Mdm2 and MdmX, that work in concert to repress p53 as a transcriptional activator and also to degrade p53 in unstressed cells. While wild-type p53 is an extensively studied and validated tumor suppressor, epidemiological studies, mouse models and cell-based assays support the likelihood that the mutant forms of p53 found in many tumors contribute to oncogenic characteristics such as malignant morphology, motility, invasion and metastasis. Our recent studies have revealed novel pathways in which p53 operates as well as new regulators of p53 and Mdm2. In each case datasets from cancer patients have supported the potential clinical relevance of our basic research findings. First, we discovered that mutant p53 regulates the malignant phenotype of breast cancer cell lines grown in 3D culture conditions (Freed-Pastor et al., Cell 2012). Expression levels of over 1000 genes are significantly altered when levels of mutant p53 are experimentally manipulated in this setting. Among the gene sets to be affected by mutant p53 is the mevalonate (MVA) pathway that is responsible for biosynthesis of cholesterol as well as key intermediates required for protein prenylation. The ability of mutant p53 to regulate the malignant morphology of breast cancer cells in 3D cultures likely requires the MVA pathway. A p53 mutant can cooperate with the SREBP2 transcription factor required for transcription of MVA genes. Breast cancer datasets indicate a correlation between mutant p53 and increased expression of some MVA genes. We are currently examining the role of wild-type p53 in regulating MVA genes and have also identified another highly cancer relevant pathway that is regulated by mutant p53. Second, we showed that TAB 1 (TGFβ-activated kinase 1 (TAK1)-binding protein 1) can bind and inhibit the E3 ligase activity of Mdm2 towards both p53 and MdmX (Zhu et al. Genes Dev 2013). We discovered that cisplatin is unique among diverse chemotherapeutic agents that were tested in requiring full levels of TAB1 to produce p53-dependent apoptosis. Two separate but possibly interrelated cell death pathways are regulated by TAB1 in cisplatin treated cells. TAB1 is required for both phosphorylation of p53 by p38 and the ability of MdmX to facilitate apoptosis in cisplatin-treated cells. TAB1 levels are reduced in a significant fraction of ovarian tumors indicating its possible role in tumor suppression. TAB1 therefore serves as a functional link between p53-MDM2 circuitry and a key MAPK signaling pathway. Elucidating the mechanism by which TAB1 regulates Mdm2 and MdmX in a cisplatin-specific manner is an ongoing focus of our research as is examining TAB1 as a potential therapeutic target. Third, we found that Nup98, a component of the nuclear pore complex is required for selective expression of a small subset of tested p53 target genes (eg. p21 and 14-3-3-sigma) in liver cancer cell lines (Singer et al., Mol. Cell 2012). Interestingly, Nup98 plays a post transcriptional role that involves stabilization of p21 mRNA via complex formation with its 3’UTR, thereby protecting it from exosomal degradation. Depending on the setting, depletion of Nup98 leads to decreased senescence or increased cell death. Nup98 expression is significantly lower than normal in hepatocellular carcinoma (HCC) tumors in mice and in a fraction of human HCCs, suggesting its role as a potential tumor suppressor. We are currently examining the roles and activities of Nup98 fusion proteins that occur in some forms of leukemia. Citation Format: Carol L. Prives. The two faces of p53: Tumor suppressor and oncogene. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr PL01-02. doi:10.1158/1538-7445.AM2014-PL01-02