Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway.
Klotho has recently emerged as a regulator of aging. To investigate the role of Klotho in the regulation of cellular senescence, we generated stable MRC-5 human primary fibroblast cells knockdown for Klotho expression by RNAi. Downregulation of Klotho dramatically induces premature senescence with a concomitant upregulation of p21. The upregulation of p21 is associated with cell cycle arrest at G1/S boundary. Knockdown of p53 in the Klotho attenuated MRC-5 cells restores normal growth and replicative potential. These results demonstrate that Klotho normally regulates cellular senescence by repressing the p53/p21 pathway. Our findings implicate Klotho as a regulator of aging in primary human fibroblasts.
de Oliveira
Rita Machado
RM
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. ritajol@mit.edu
D002454:Cell Differentiation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D000090265:Klotho Proteins; D034622:RNA Interference; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D050759:Cyclin-Dependent Kinase Inhibitor p21; D007328:Insulin; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D005966:Glucuronidase; D000090265:Klotho Proteins