Pin1-mediated Runx2 modification is critical for skeletal development

• Published in: Journal of cellular physiology Vol. 228; no. 12; pp. 2377 - 2385
• Main Authors: Yoon, Won-Joon, Islam, Rabia, Cho, Young-Dan, Woo, Kyung-Mi, Baek, Jeong-Hwa, Uchida, Takafumi, Komori, Toshihisa, van Wijnen, Andre, Stein, Janet L., Lian, Jane B., Stein, Gary S., Choi, Je-Yong, Bae, Suk-Chul, Ryoo, Hyun-Mo
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.12.2013; Wiley Subscription Services, Inc
• Subjects: Animals; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell Line; Cleidocranial Dysplasia - genetics; Cleidocranial Dysplasia - metabolism; Cleidocranial Dysplasia - physiopathology; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; HEK293 Cells; Humans; Mice; Mutation; NIMA-Interacting Peptidylprolyl Isomerase; Osteoblasts - metabolism; Osteoblasts - physiology; Osteogenesis - genetics; Osteogenesis - physiology; Peptidylprolyl Isomerase - genetics; Peptidylprolyl Isomerase - metabolism; Phenotype; Phosphorylation - genetics; Proteolysis; Ubiquitin - genetics; Ubiquitin - metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.24403

Runx2 is the master transcription factor for bone formation. Haploinsufficiency of RUNX2 is the genetic cause of cleidocranial dysplasia (CCD) that is characterized by hypoplastic clavicles and open fontanels. In this study, we found that Pin1, peptidyl prolyl cis–trans isomerase, is a critical regulator of Runx2 in vivo and in vitro. Pin1 mutant mice developed CCD‐like phenotypes with hypoplastic clavicles and open fontanels as found in the Runx2+/− mice. In addition Runx2 protein level was significantly reduced in Pin1 mutant mice. Moreover Pin1 directly interacts with the Runx2 protein in a phosphorylation‐dependent manner and subsequently stabilizes Runx2 protein. In the absence of Pin1, Runx2 is rapidly degraded by the ubiquitin‐dependent protein degradation pathway. However, Pin1 overexpression strongly attenuated uniquitin‐dependent Runx2 degradation. Collectively conformational change of Runx2 by Pin1 is essential for its protein stability and possibly enhances the level of active Runx2 in vivo. J. Cell. Physiol. 228: 2377–2385, 2013. © 2013 Wiley Periodicals, Inc.