A Distinct Role for Pin1 in the Induction and Maintenance of Pluripotency

• DOI: 10.1074/jbc.m110.187989
• Publication Date: 2011-02-05T02:42:52Z
• Authors: Mayuko Nishi; Hidenori Akutsu; Shinji Masui; Asami Kondo; Yoji Nagashima; Hirokazu Kimura; Kilian Perrem; Yasushi Shigeri; Masashi Toyoda; Akiko Okayama; Hisashi Hirano; Akihiro Umezawa; Naoki Yamamoto; Sam W. Lee; Akihide Ryo
• Keywords: 0301 basic medicine; Amino Acid Motifs; Induced Pluripotent Stem Cells; 500; Cell Differentiation; Peptidylprolyl Isomerase; Cell Line; NIMA-Interacting Peptidylprolyl Isomerase; 03 medical and health sciences; Humans; Phosphorylation; Octamer Transcription Factor-3; Cell Proliferation; Signal Transduction

The prominent characteristics of pluripotent stem cells are their unique capacity to self-renew and pluripotency. Although pluripotent stem cell proliferation is maintained by specific intracellular phosphorylation signaling events, it has not been well characterized how the resulting phosphorylated proteins are subsequently regulated. We here report that the peptidylprolyl isomerase Pin1 is indispensable for the self-renewal and maintenance of pluripotent stem cells via the regulation of phosphorylated Oct4 and other substrates. Pin1 expression was found to be up-regulated upon the induction of induced pluripotent stem (iPS) cells, and the forced expression of Pin1 with defined reprogramming factors was observed to further enhance the frequency of iPS cell generation. The inhibition of Pin1 activity significantly suppressed colony formation and induced the aberrant differentiation of human iPS cells as well as murine ES cells. We further found that Pin1 interacts with the phosphorylated Ser(12)-Pro motif of Oct4 and that this in turn facilitates the stability and transcriptional activity functions of Oct4. Our current findings thus uncover an atypical role for Pin1 as a putative regulator of the induction and maintenance of pluripotency via the control of phosphorylation signaling. These data suggest that the manipulation of Pin1 function could be a potential strategy for the stable induction and proliferation of human iPS cells.