title: p18 inhibits reprogramming through inactivation of Cdk4/6.
abstract: Pluripotent stem cells (PSCs), including embryonic and induced pluripotent stem cells (iPSCs), show atypical cell cycle regulation characterized by a high proliferation rate and a shorter G1 phase compared with somatic cells. The mechanisms by which somatic cells remodel their cell cycle to achieve the high proliferation rate of PSCs during reprogramming are unclear. Here we identify that the Ink4 protein p18, which is expressed at high levels in somatic cells but at low levels in PSCs, is a roadblock to successful reprogramming. Mild inhibition of p18 expression enhances reprogramming efficiency, while ectopic expression of p18 completely blocks reprogramming. Mechanistic studies show that expression of wild-type p18, but not a p18(D68N) mutant which cannot inhibit Cdk4/6, down-regulates expression of Cdk4/6 target genes involved in DNA synthesis (TK, TS, DHFR, PCNA) and cell cycle regulation (CDK1 and CCNA2) and thus inhibits reprogramming. These results indicate that p18 blocks reprogramming by targeting Cdk4/6-mediated cell cycle regulation. Taken together, our results define a novel pathway that inhibits somatic cell reprogramming, and provide a new target to enhance reprogramming efficiency.
authors.affiliation: School of Biological Sciences, University of Science and Technology of China, Hefei 230026, China.|State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jiani
authors.initials: J
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yaqiong
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Biological Sciences, University of Science and Technology of China, Hefei 230026, China.|State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Tongbiao
authors.initials: T
authors.lastname: Zhao
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D065150:Cellular Reprogramming; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis* / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D054778:NM23 Nucleoside Diphosphate Kinases / Q000096:biosynthesis* / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000378:metabolism*
chemical_list: D054778:NM23 Nucleoside Diphosphate Kinases; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C517941:Nme2 protein, mouse