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You, H, Jang, Y, You-Ten, AI, Okada, H, Liepa, J, Wakeham, A, Zaugg, K and Mak, TW (2004) p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Proc. Natl. Acad. Sci. U.S.A. 101:14057-62
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.
Animals; Antineoplastic Agents/toxicity; Blotting, Northern; Cells, Cultured; DNA Damage/physiology; Embryo, Mammalian/cytology; Enzyme Induction/drug effects; Enzyme Induction/physiology; Enzyme Induction/radiation effects; Etoposide/toxicity; Fibroblasts/metabolism; Fibroblasts/physiology; Forkhead Transcription Factors; Humans; Immediate-Early Proteins; Immunoblotting; Mice; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Phosphorylation; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; RNA Interference; Transcription Factors/antagonists & inhibitors; Transcription Factors/genetics; Transcription Factors/metabolism; Tumor Necrosis Factor-alpha/toxicity; Tumor Suppressor Protein p53/physiology
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