A Distinct Role for Pin1 in the Induction and Maintenance of Pluripotency
A Distinct Role for Pin1 in the Induction and Maintenance of Pluripotency
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DOI：
10.1074/jbc.m110.187989
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发表时间：
2011-04-01
影响因子：
4.8
通讯作者：
Ryo, Akihide
中科院分区：
文献类型：
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作者：
Nishi, Mayuko;Akutsu, Hidenori;Ryo, Akihide
多能干细胞的突出特点是其独特的自我更新能力和多能性。虽然多能干细胞的增殖是通过特定的细胞内磷酸化信号事件来维持的，但目前还没有很好地描述磷酸化蛋白随后是如何被调节的。我们在这里报道了肽基脯氨酸异构酶Pin1通过磷酸化Oct4和其他底物的调节对多能干细胞的自我更新和维持是必不可少的。Pin1的表达在诱导多能干细胞（induced pluripotent stem, iPS）的诱导过程中被上调，而Pin1在定义了重编程因子的情况下被强制表达，进一步提高了iPS细胞的生成频率。抑制Pin1活性可显著抑制人类iPS细胞和小鼠ES细胞的集落形成并诱导其异常分化。我们进一步发现Pin1与Oct4磷酸化的Ser(12)-Pro基序相互作用，从而促进Oct4的稳定性和转录活性功能。因此，我们目前的研究结果揭示了Pin1作为一种通过控制磷酸化信号传导来诱导和维持多能性的假定调节剂的非典型作用。这些数据表明，操纵Pin1功能可能是稳定诱导和增殖人类iPS细胞的潜在策略。
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.