title: The p53-PUMA axis suppresses iPSC generation.
abstract: Mechanisms underlying the reprogramming process of induced pluripotent stem cells remain poorly defined. Like tumorigenesis, generation of induced pluripotent stem cells was shown to be suppressed by the Trp53 (p53) pathway, at least in part via p21Cdkn1a (p21)-mediated cell cycle arrest. Here we examine the role of PUMA, a pro-apoptotic mediator of p53, during somatic reprogramming in comparison to p21 in the p53 pathway. Using mouse strains deficient in these molecules, we demonstrate that PUMA is an independent mediator of the negative effect of p53 on induced pluripotent stem cell induction. PUMA deficiency leads to a better survival rate associated with reduced DNA damage and fewer chromosomal aberrations in induced pluripotent stem cells, whereas loss of p21 or p53 results in an opposite outcome. Given these new findings, PUMA may serve as a distinct and more desirable target in the p53 pathway for induced pluripotent stem cell generation, thereby having important implications for potential therapeutic applications of induced pluripotent stem cells.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road No. 288, Tianjin 300020, China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Li
authors.forename: Haizhong
authors.initials: H
authors.lastname: Feng
authors.forename: Haihui
authors.initials: H
authors.lastname: Gu
authors.forename: Dale W
authors.initials: DW
authors.lastname: Lewis
authors.forename: Youzhong
authors.initials: Y
authors.lastname: Yuan
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Haizi
authors.initials: H
authors.lastname: Cheng
authors.forename: Weimin
authors.initials: W
authors.lastname: Miao
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Gollin
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D002869:Chromosome Aberrations; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics*; D004249:DNA Damage; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins