title: p53 regulates autophagic activity in senescent rat mesenchymal stromal cells.
abstract: The tumor suppressor protein p53 is an important player in the regulation of cell senescence, its functions are largely carried out by modulating its downstream genes. Emerging evidence has suggested that senescence and autophagy appear to be regulated by overlapping signaling pathways. Furthermore, autophagy markers have been observed in senescent cells. In this study, we sought to explore the effects of the expression pattern and function of p53 on the activity of autophagy and replicative senescence in bone marrow derived mesenchymal stromal cells (BMSCs). We found that more than 85% of BMSCs stained positive for SA-β-gal at passage 6 (senescent BMSCs) with increased expressions of senescence related genes (p16(ink4a) and p21(waf1)). These results were accompanied by the up-regulation of p53, down-regulation of mammalian target of rapamycin (mTOR) and phosphorylation of Rb. Senescent BMSCs displayed an increased monodansylcadaverine (MDC) staining and autophagy related genes (LC3 and atg12) level compared with BMSCs at passage 2. Knockdown of p53 alleviated the senescent state and reduced autophagic activity during the progression of BMSC senescence, which was accompanied by significantly up-regulated levels of mTOR and phosphorylation of Rb. These results demonstrate that autophagy increases when BMSCs enter the replicative senescence state, and p53 contributes a crucial role in the up-regulation of autophagy in this state.
authors.affiliation: Department of Anatomy and Embryology, Wuhan University School of Medicine, Wuhan University, Wuhan, Hubei 430071, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Anatomy and Embryology, Wuhan University School of Medicine, Wuhan University, Wuhan, Hubei 430071, PR China.
authors.forename: Yueshan
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Qianjin Community Health Service Center of Jianghan District, Wuhan, Hubei 430022, PR China.
authors.forename: Chenghua
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Anatomy and Embryology, Wuhan University School of Medicine, Wuhan University, Wuhan, Hubei 430071, PR China. Electronic address: chengjunhu@whu.edu.cn.
authors.forename: Chengjun
authors.initials: C
authors.lastname: Hu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D059630:Mesenchymal Stem Cells / Q000473:pathology / Q000502:physiology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D016160:Retinoblastoma Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; Mesenchymal stromal cells; Senescence; p53