Abstract
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.
Highlights
The prominent characteristics of pluripotent stem cells are their unique capacity to self-renew and pluripotency
Pin1 Is Induced upon Cellular Reprogramming and Enhances Generation of induced pluripotent stem (iPS) Cells—To examine the role of Pin1 in cellular reprogramming and pluripotency, we initially investigated the expression levels of this prolyl isomerase in human iPS cells
Immunofluorescent analysis further revealed that Pin1 is selectively expressed in SOX2-positive pluripotent stem cells, whereas its expression was found to be significantly suppressed in the surrounding SOX2-negative differentiated cells (Fig. 1B)
Summary
Our current findings uncover an atypical role for Pin as a putative regulator of the induction and maintenance of pluripotency via the control of phosphorylation signaling These data suggest that the manipulation of Pin function could be a potential strategy for the stable induction and proliferation of human iPS cells. A pivotal signaling mechanism that controls the function of phosphorylated proteins is the cis-trans isomerization of phosphorylated Ser/Thr-Pro motifs by the peptidylprolyl isomerase Pin1 [13, 14] This modification regulates multiple intracellular signaling pathways, including ErbB2/Ras, Wnt/catenin, and NF-B, and plays an important role in the etiology of several human diseases [15,16,17,18]. Our present data suggest that Pin is a putative regulator of the selfrenewal and proliferation of pluripotent stem cells
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