Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc
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Luana D’Artista1,2, Andrea Bisso1, Andrea Piontini2, Mirko Doni2, Alessandro Verrecchia2, Theresia R. Kress1, Marco J. Morelli1, Giannino Del Sal3,4, Bruno Amati1,2, Stefano Campaner1
1Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
2Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy
3Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy
4Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste, Italy
Bruno Amati, e-mail: [email protected]
Stefano Campaner, e-mail: [email protected]
Keywords: c-myc, Pin1, lymphoma, proliferation
Received: January 17, 2016 Accepted: February 21, 2016 Published: March 02, 2016
The c-myc proto-oncogene is activated by translocation in Burkitt’s lymphoma and substitutions in codon 58 stabilize the Myc protein or augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 and Thr 58 provides a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, the role of Pin1 in Myc-induced lymphomagenesis remains unknown. We show here that genetic ablation of Pin1 reduces lymphomagenesis in Eμ-myc transgenic mice. In both Pin1-deficient B-cells and MEFs, the proliferative response to oncogenic Myc was selectively impaired, with no alterations in Myc-induced apoptosis or mitogen-induced cell cycle entry. This proliferative defect wasn’t attributable to alterations in either Ser 62 phosphorylation or Myc-regulated transcription, but instead relied on the activity of the ARF-p53 pathway. Pin1 silencing in lymphomas retarded disease progression in mice, making Pin1 an attractive therapeutic target in Myc-driven tumors.
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