p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming

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Martin-Lopez , M , Maeso-Alonso , L , Fuertes-Alvarez , S , Balboa , D , Rodriguez-Cortez , V , Weltner , J , Diez-Prieto , I , Davis , A , Wu , Y , Otonkoski , T , Flores , E R , Menendez , P , Marques , M M & Marin , M C 2017 , ' p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming ' , Cell Death and Disease , vol. 8 , 3034 . https://doi.org/10.1038/cddis.2017.432

Title: p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming
Author: Martin-Lopez, Marta; Maeso-Alonso, Laura; Fuertes-Alvarez, Sandra; Balboa, Diego; Rodriguez-Cortez, Virginia; Weltner, Jere; Diez-Prieto, Inmaculada; Davis, Andrew; Wu, Yaning; Otonkoski, Timo; Flores, Elsa R.; Menendez, Pablo; Marques, Margarita M.; Marin, Maria C.
Contributor: University of Helsinki, University of Helsinki
University of Helsinki, Research Programs Unit
University of Helsinki, University of Helsinki
Date: 2017-09
Language: eng
Number of pages: 13
Belongs to series: Cell Death and Disease
ISSN: 2041-4889
URI: http://hdl.handle.net/10138/231138
Abstract: The generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming holds great potential for modeling human diseases. However, the reprogramming process remains very inefficient and a better understanding of its basic biology is required. The mesenchymal-to-epithelial transition (MET) has been recognized as a crucial step for the successful reprogramming of fibroblasts into iPSCs. It has been reported that the p53 tumor suppressor gene acts as a barrier of this process, while its homolog p63 acts as an enabling factor. In this regard, the information concerning the role of the third homolog, p73, during cell reprogramming is limited. Here, we derive total Trp73 knockout mouse embryonic fibroblasts, with or without Trp53, and examine their reprogramming capacity. We show that p73 is required for effective reprogramming by the Yamanaka factors, even in the absence of p53. Lack of p73 affects the early stages of reprogramming, impairing the MET and resulting in altered maturation and stabilization phases. Accordingly, the obtained p73-deficient iPSCs have a defective epithelial phenotype and alterations in the expression of pluripotency markers. We demonstrate that p73 deficiency impairs the MET, at least in part, by hindering BMP pathway activation. We report that p73 is a positive modulator of the BMP circuit, enhancing its activation by DNp73 repression of the Smad6 promoter. Collectively, these findings provide mechanistic insight into the MET process, proposing p73 as an enhancer of MET during cellular reprogramming.
Subject: PLURIPOTENT STEM-CELLS
SELF-RENEWAL
HUMAN FIBROBLASTS
IPS CELLS
IN-VIVO
DIFFERENTIATION
P53
GENERATION
MOUSE
SUPPRESSION
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
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