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

Abstract

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.

Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells

“…Pin1 is hyperactivated in most human cancers and correlates with poor clinical outcome 6 , 7 , 25 , whereas humans with genetic polymorphisms that reduce PIN1 expression have a lower risk for multiple cancers 6 , 7 , 25 . Pin1 knockout (−/−, KO) mice are highly resistant to tumorigenesis even amid overexpression of oncogenes such as HER2 27 , RAS 27 , Myc 28 , or after mutation 29 or ablation 30 of tumor suppressors such as p53. Conversely, Pin1 overexpression disrupts cell cycle coordination leading to chromosome instability and cancer development 31 .…”

Prolyl isomerase Pin1: a promoter of cancer and a target for therapy

“…In contrast, it is highly expressed in most cancers, especially in cancer stem cells (CSCs), and negatively related to the clinical prognosis 30 – 32 . The depletion of Pin1 significantly inhibits tumorigenesis in the mice models that are derived by mutation of p53 33 , activation of HER2/RAS 34 or constitutive expression of c-Myc 35 . Additionally, many Pin1-targeted inhibitors, including all trans retinoic acid (ATRA) 36 , juglone 37 , and KPT-6566 38 , have showed cancer suppression ability in multiple researches (Table 1 ).…”

LigGrep: a tool for filtering docked poses to improve virtual-screening hit rates

“…Hs Pin1p is upregulated in many cancers, likely because many of its targets contribute to cancer pathogenesis. Reduced Hs Pin1p activity protects against cancer progression [ 38 , 42 – 44 ], so much effort has been invested in developing Hs Pin1p inhibitors [ 38 ].…”