Abstract IA10: Post-translational regulation of MYC's oncogenic activity

In response to growth stimulatory signals in normal cells or in transformed cells with constitutive signaling, the c-Myc oncoprotein is post-translationally stabilized through enhanced phosphorylation at the conserved Serine 62 residue. In addition to increasing c-Myc stability, phosphorylation at Serine 62 (pS62-Myc), in conjunction with Proline 63 isomerization mediated by the Pin1 Proline Isomerase, also increases the rate of recruitment of newly synthesized c-Myc to its target genes involved in pro-proliferative phenotypes, enhancing their expression. In normal cells, phosphorylation of S62 primes phosphorylation at a second conserved residue, Threonine 58 (pT58), which then enhance c-Myc degradation by facilitating a second Pin1-mediated isomerization event, which promotes Protein Phosphatase 2A (PP2A-B56α)-mediated dephosphorylation of Serine 62 and recruits the E3 ubiquitin ligase, SCFFbw7. In cancer cell lines as well as patient tumor samples pS62-Myc is elevated relative to non-transformed cell lines or adjacent normal tissue. In order to study the role of pS62-Myc in vivo, we created c-Myc knock-in mice that express either Myc wild-type (WT) or the MycT58A or MycS62A phosphorylation mutant from the ROSA26 locus in response to Cre-recombinase. Analysis of these mice revealed increased tumorigenic potential of MycT58A, which has constitutive S62 phosphorylation as it is resistant to PP2A-mediated S62 dephosphorylation. Together, this research has revealed an important role for S62 phosphorylation and Pin1-mediated isomerization in the tumorigenic activity of c-Myc, which presents new strategies to target c-Myc by inhibiting these post-translational activation steps. Thus, we are currently testing the therapeutic efficacy of PP2A activation and Pin1 inhibition in mouse models of c-Myc-driven tumorigenesis. To create physiologically relevant c-Myc-driven tumor models that engage post-translational activation of c-Myc, we have crossed our ROSA-LSL-MycWT mice with mice carrying organ-relevant oncogenic signaling transgenes. Thus far, we have generated mouse models of Her2+ and Triple Negative breast cancer, and pancreatic cancer. We have demonstrated dramatic tumor growth inhibition with a novel, orally available small molecule PP2A activator drug in these mouse models. Citation Format: Rosalie Sears, Amy Farrell, Xiaoyan Wang, Juan Liang, Mahnaz Janghorban, Yulong Su, Brittany Allen-Petersen, Michael Ohlemeyer, Narla Goutham. Post-translational regulation of MYC9s oncogenic activity. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA10.