Differential regulation of cellular senescence and differentiation by prolyl isomerase Pin1 in cardiac progenitor cells

Haruhiro Toko, Nirmala Hariharan, Mathias H. Konstandin, Lucia Ormachea, Michael McGregor, Natalie A. Gude, Balaji Sundararaman, Eri Joyo, Anya Y. Joyo, Brett Collins, Shabana Din, Sadia Mohsin, Takafumi Uchida, Mark A. Sussman

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Autologous c-kit+ cardiac progenitor cells (CPCs) are currently used in the clinic to treat heart disease. CPC-based regeneration may be further augmented by better understanding molecular mechanisms of endogenous cardiac repair and enhancement of pro-survival signaling pathways that antagonize senescence while also increasing differentiation. The prolyl isomerase Pin1 regulates multiple signaling cascades by modulating protein folding and thereby activity and stability of phosphoproteins. In this study, we examine the heretofore unexplored role of Pin1 in CPCs. Pin1 is expressed in CPCs in vitro and in vivo and is associated with increased proliferation. Pin1 is required for cell cycle progression and loss of Pin1 causes cell cycle arrest in the G 1 phase in CPCs, concomitantly associated with decreased expression of Cyclins D and B and increased expression of cell cycle inhibitors p53 and retinoblastoma (Rb). Pin1 deletion increases cellular senescence but not differentiation or cell death of CPCs. Pin1 is required for endogenous CPC response as Pin1 knock-out mice have a reduced number of proliferating CPCs after ischemic challenge. Pin1 overexpression also impairs proliferation and causes G2/M phase cell cycle arrest with concurrent down-regulation of Cyclin B, p53, and Rb. Additionally, Pin1 overexpression inhibits replicative senescence, increases differentiation, and inhibits cell death of CPCs, indicating that cell cycle arrest caused by Pin1 overexpression is a consequence of differentiation and not senescence or cell death. In conclusion, Pin1 has pleiotropic roles in CPCs and may be a molecular target to promote survival, enhance repair, improve differentiation, and antagonize senescence.

Original languageEnglish (US)
Pages (from-to)5348-5356
Number of pages9
JournalJournal of Biological Chemistry
Volume289
Issue number9
DOIs
StatePublished - Feb 28 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Toko, H., Hariharan, N., Konstandin, M. H., Ormachea, L., McGregor, M., Gude, N. A., Sundararaman, B., Joyo, E., Joyo, A. Y., Collins, B., Din, S., Mohsin, S., Uchida, T., & Sussman, M. A. (2014). Differential regulation of cellular senescence and differentiation by prolyl isomerase Pin1 in cardiac progenitor cells. Journal of Biological Chemistry, 289(9), 5348-5356. https://doi.org/10.1074/jbc.M113.526442