Luana D'Artista

First name
Luana
Last name
D'Artista
Year of Study
Thesis Title
The role of Pin1 in Myc induced lymphomagenesis
Thesis Abstract
The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma and is frequently subject to secondary mutations. Substitutions in codon 58, in particular, stabilize the c-Myc protein (Myc) 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. We observed 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, in the absence of changes in either steady-state Myc levels or Ser 62 phosphorylation. Similarly, in Pin1-/- mouse embryo fibroblasts (MEFs), prolonged Myc activation inhibited proliferation. In either B-cells or MEFs, Myc-induced apoptosis occurred independently from Pin1. Loss of p53 rescued proliferative defect of Eμ-myc Pin1-/- B cells and of Pin1-/- MEFs upon Myc activation. This result suggests the existence of a p53 dependent checkpoint in the Pin1-/- cells that inhibits Myc driven proliferation: this mechanism blocked tumorigenesis in the E-myc Pin1-/- mice. The origin of this arrest is under investigation. Although Eμ-myc Pin1-/- B cells showed reduced activation of Mycinduced mRNAs relative to Eμ-myc Pin1+/+ cells, experiments in MEFs and R26MycER B cells demonstrated that the overall transcriptional activity of Myc was independent from Pin1. Thus, while Pin1 is not essential for normal cell growth and mouse development, it is required to support the oncogenic activity of Myc in B cells. Moreover, Eμ-myc lymphoma cells were sensitive to Pin1 inhibition, making Pin1 an attractive therapeutic target in Myc-driven tumors.
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