p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1.
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.
You
Han
H
Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Suite 706, Toronto, ON, Canada M5G 2C1.
Jang
YingJu
Y
You-Ten
Annick Itie
AI
Okada
Hitoshi
H
Liepa
Jennifer
J
Wakeham
Andrew
A
Zaugg
Kathrin
K
Mak
Tak W
TW
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D015152:Blotting, Northern; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005047:Etoposide / Q000633:toxicity; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006801:Humans; D017874:Immediate-Early Proteins; D015151:Immunoblotting; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034622:RNA Interference; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000099184:Serum-Glucocorticoid Regulated Kinases
D000970:Antineoplastic Agents; D005047:Etoposide; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D000099184:Serum-Glucocorticoid Regulated Kinases; C474033:FoxO3 protein, mouse; C494918:AKT1 protein, human