| First Author | Li L | Year | 2011 |
| Journal | Cancer Res | Volume | 71 |
| Issue | 24 | Pages | 7694-704 |
| PubMed ID | 22025562 | Mgi Jnum | J:178847 |
| Mgi Id | MGI:5300413 | Doi | 10.1158/0008-5472.CAN-11-1714 |
| Citation | Li L, et al. (2011) GLIPR1 Suppresses Prostate Cancer Development through Targeted Oncoprotein Destruction. Cancer Res 71(24):7694-704 |
| abstractText | Downregulation of the proapoptotic p53 target gene glioma pathogenesis-related protein 1 (GLIPR1) occurs frequently in prostate cancer, but the functional meaning of this event is obscure. Here, we report the discovery of functional relationship between GLIPR1 and c-Myc in prostate cancer where c-Myc is often upregulated. We found that the expression of GLIPR1 and c-Myc were inversely correlated in human prostate cancer. Restoration of GLIPR1 expression in prostate cancer cells downregulated c-myc levels, inhibiting cell-cycle progression. Downregulation was linked to a reduction in beta-catenin/TCF4-mediated transcription of the c-myc gene, which was caused by GLIPR1-mediated redistribution of casein kinase 1alpha (CK1alpha) from the Golgi apparatus to the cytoplasm where CK1alpha could phosphorylate beta-catenin and mediate its destruction. In parallel, GLIPR1 also promoted c-Myc protein ubiquitination and degradation by glycogen synthase kinase-3alpha- and/or CK1alpha-mediated c-Myc phosphorylation. Notably, genetic ablation of the mouse homolog of Glipr1 cooperated with c-myc overexpression to induce prostatic intraepithelial neoplasia and prostate cancer. Together, our findings provide evidence for CK1alpha-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1alpha phosphorylation site for c-Myc degradation. Furthermore, they reveal parallel mechanisms of c-myc downregulation by GLIPR1 that when ablated in the prostate are sufficient to drive c-Myc expression and malignant development. Cancer Res; 71(24); 7694-704. (c)2011 AACR. |
