title: Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation.
abstract: The homolog of p53 gene, p63, encodes multiple p63 protein isoforms. TAp63 proteins contain an N-terminal transactivation domain similar to that of p53 and function as tumor suppressors; whereas ΔNp63 isoforms, which lack the intact N-terminal transactivation domain, are associated with human tumorigenesis. Accumulating evidence demonstrating the important roles of p63 in development and cancer development, the regulation of p63 proteins, however, is not fully understood. In this study, we show that peptidyl-prolyl isomerase Pin1 directly binds to and stabilizes TAp63α and ΔNp63α via inhibiting the proteasomal degradation mediated by E3 ligase WWP1. We further show that Pin1 specifically interacts with T538P which is adjacent to the P550PxY543 motif, and disrupts p63α-WWP1 interaction. In addition, while Pin1 enhances TAp63α-mediated apoptosis, it promotes ΔNp63α-induced cell proliferation. Furthermore, knockdown of Pin1 in FaDu cells inhibits tumor formation in nude mice, which is rescued by simultaneous knockdown of WWP1 or ectopic expression of ΔNp63α. Moreover, overexpression of Pin1 correlates with increased expression of ΔNp63α in human oral squamous cell carcinoma samples. Together, these results suggest that Pin1-mediated modulation of ΔNp63α may have a causative role in tumorigenesis.
authors: Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
authors: C
authors: C
authors: Li
authors: D L
authors: DL
authors: Chang
authors: Z
authors: Z
authors: Yang
authors: J
authors: J
authors: Qi
authors: R
authors: R
authors: Liu
authors: H
authors: H
authors: He
authors: D
authors: D
authors: Li
authors: Z X
authors: ZX
authors: Xiao
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D015151:Immunoblotting; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse