P53-dependent Inhibition of FKHRL1 in Response to DNA Damage Through Protein Kinase SGK1

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Sep 24

PMID 15383658

Citations 52

Authors

Han You

YingJu Jang

Annick Itie You-Ten

Hitoshi Okada

Jennifer Liepa

Andrew Wakeham

Kathrin Zaugg

Tak W Mak

Affiliations

Soon will be listed here.

Abstract

FKHRL1 (FOXO3a) and p53 are two potent stress-response regulators. Here we show that these two transcription factors exhibit "crosstalk" in vivo. In response to DNA damage, p53 activation led to FKHRL1 phosphorylation and subcellular localization change, which resulted in inhibition of FKHRL1 transcription activity. AKT was dispensable for p53-dependent suppression of FKHRL1. By contrast, serum- and glucocorticoid-inducible kinase 1 (SGK1) was significantly induced in a p53-dependent manner after DNA damage, and this induction was through extracellular signal-regulated kinase 1/2-mediated posttranslational regulation. Furthermore, inhibition of SGK1 expression by a small interfering RNA knockdown experiment significantly decreased FKHRL1 phosphorylation in response to DNA damage. Taken together, our observations reveal previously unrecognized crosstalk between p53 and FKHRL1. Moreover, our findings suggest a new pathway for understanding aging and the age dependency of human diseases governed by these two transcription factors.

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