Abstract B03: Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc

The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma, where it is also frequently subject to secondary mutations. Substitutions in codon 58, in particular, stabilize the Myc protein and augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 primes phosphorylation of Thr 58, providing a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, genetic data are missing to address whether Pin1 influences Myc-induced lymphomagenesis. Here, we show that genetic ablation of Pin1 in Eµ-myc transgenic mice starkly reduced lymphoma onset and penetrance. In pre-malignant Pin1 deficient B cells, the proliferative response to Myc was selectively impaired, while Myc-induced apoptosis was intact. This phenotype was not the result of deregulated levels of Ser 62 phosphorylation in the Pin1-/- background. Similar results were observed in Pin1-/- mouse embryo fibroblasts (MEFs), where prolonged Myc activation inhibited proliferation. In either B cells or MEFs, loss of Pin1 did not affect mitogen-induced cell cycle entry, an effect that relies on endogenous Myc activity. Thus, our data unravel the existence of a synthetic-lethal interaction between deletion of Pin1 and oncogenic activation of Myc. Myc-induced oncogenic stress is linked to the induction of the Arf/p53 pathway, which is critical for tumor suppression in Eµ-myc mice. The selective pressure to inactivat...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Modeling Myc in Mouse: Poster Presentations - Proffered Abstracts Source Type: research