title: p53 counteracts reprogramming by inhibiting mesenchymal-to-epithelial transition.
abstract: The process of somatic cell reprogramming is gaining increasing interest as reprogrammed cells are considered to hold a great therapeutic potential. However, with current technologies this process is relatively inefficient. Recent studies reported that inhibition of the p53 tumor suppressor profoundly facilitates reprogramming and attributed this effect to the ability of p53 to restrict proliferation and induce apoptosis. Given that mesenchymal-to-epithelial transition (MET) was recently shown to be necessary for reprogramming of fibroblasts, we investigated whether p53 counteracts reprogramming by affecting MET. We found that p53 restricts MET during the early phases of reprogramming and that this effect is primarily mediated by the ability of p53 to inhibit Klf4-dependent activation of epithelial genes. Moreover, transcriptome analysis revealed a large transcriptional signature enriched with epithelial genes, which is markedly induced by Klf4 exclusively in p53(-/-) cells. We also found that the expression of the epithelial marker E-Cadherin negatively correlates with p53 activity in a variety of mesenchymal cells even before the expression of reprogramming factors. Finally, we demonstrate that the inhibitory effect of p53 on MET is mediated by p21. We conclude that inhibition of the p53-p21 axis predisposes mesenchymal cells to the acquisition of epithelial characteristics and renders them more prone to reprogramming. Our study uncovers a novel mechanism by which p53 restrains reprogramming and highlights the role of p53 in regulating cell plasticity.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. ranbroshran@gmail.com
authors.forename: R
authors.initials: R
authors.lastname: Brosh
authors.forename: Y
authors.initials: Y
authors.lastname: Assia-Alroy
authors.forename: A
authors.initials: A
authors.lastname: Molchadsky
authors.forename: C
authors.initials: C
authors.lastname: Bornstein
authors.forename: E
authors.initials: E
authors.lastname: Dekel
authors.forename: S
authors.initials: S
authors.lastname: Madar
authors.forename: Y
authors.initials: Y
authors.lastname: Shetzer
authors.forename: N
authors.initials: N
authors.lastname: Rivlin
authors.forename: N
authors.initials: N
authors.lastname: Goldfinger
authors.forename: R
authors.initials: R
authors.lastname: Sarig
authors.forename: V
authors.initials: V
authors.lastname: Rotter
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53