MiR-138 promotes induced pluripotent stem cell generation through the regulation of the p53 signaling.
Induced pluripotent stem (iPS) cells, especially those reprogrammed from patient somatic cells, have a great potential usage in regenerative medicine. The expression of p53 has been proven as a key barrier limiting iPS cell generation, but how p53 is regulated during cell reprogramming remains unclear. In this study, we found that the ectopic expression of miR-138 significantly improved the efficiency of iPS cell generation via Oct4, Sox2, and Klf4, with or without c-Myc (named as OSKM or OSK, respectively), without sacrificing the pluripotent characteristics of the generated iPS cells. Exploration of the mechanism showed that miR-138 directly targeted the 3' untranslated region (UTR) of p53, significantly decreasing the expression of p53 and its downstream genes. Furthermore, the ectopic expression of p53 having a mutant 3'-UTR, which cannot be bound by miR-138, seriously impaired the effect of miR-138 on p53 signaling and OSKM-initiated somatic cell reprogramming. Combined with the fact that miR-138 is endogenously expressed in fibroblasts, iPS cells, and embryonic stem cells, our study demonstrated that regulation of the p53 signaling pathway and promotion of iPS cell generation represent an unrevealed important function of miR-138.
Clinical and Translational Research Center of Shanghai First Maternity & Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, People's Republic of China.
Dan
D
Ye
Guiying
G
Wang
Yang
Y
Liu
Wenfei
W
Huang
Minjuan
M
Wu
Songcheng
S
Zhu
Wenwen
W
Jia
An-Mei
AM
Deng
Houqi
H
Liu
Jiuhong
J
Kang
D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology; D015536:Down-Regulation; D055786:Gene Knockout Techniques; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53