NAMPT/SIRT2–mediated inhibition of the p53-p21 signaling pathway is indispensable for maintenance and hematopoietic differentiation of human iPS cells

Abstract

Background: Nicotinamide phosphoribosyltransferase (NAMPT) regulates cellular functions through the protein deacetylation activity of nicotinamide adenine dinucleotide (NAD+)-dependent sirtuins (SIRTs). SIRTs regulate functions of histones and none-histone proteins. The role of NAMPT/SIRTs pathway in the regulation of maintenance and differentiation of human induced pluripotent stem (iPS) cells is not fully elucidated. Methods: We evaluated the effects of specific inhibitors of NAMPT-, or SIRT2 on the pluripotency, proliferation, survival and hematopoietic differentiation of human iPS cells. We also studied the molecular mechanism downstream of NAMPT/SIRTs in iPS cells. Results: We demonstrated that NAMPT is indispensable for the maintenance, survival and hematopoietic differentiation of induced pluripotent stem (iPS) cells. We found that inhibition of NAMPT or SIRT2 in iPS cells induces p53 protein by promoting its lysine acetylation. This leads to activation of the p53 target, p21, with subsequent cell cycle arrest and induction of apoptosis in iPS cells. NAMPT and SIRT2 inhibition also affects hematopoietic differentiation of iPS cells in an embryoid body (EB)-based cell culture system. Conclusions: Our data demonstrate the essential role of the NAMPT/SIRT2/p53/p21 signaling axis in the maintenance and hematopoietic differentiation of iPS cells.

Astragalin Inhibits the Proliferation and Migration of Human Colon Cancer HCT116 Cells by Regulating the NF-κB Signaling Pathway

“…P53 is an important anticancer protein and also repairs the cell genes. P53 could target p21 with subsequent cell cycle arrest and induced cell apoptosis ( Xu et al, 2021 ). Therefore, in this study, we investigated the effect of astragalin on cell apoptosis and cell cycle on HCT116 cells.…”