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

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P53-Dependent Inhibition of FKHRL1 in Response to DNA Damage Through Protein Kinase SGK1 p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1 Han You, YingJu Jang, Annick Itie You-Ten, Hitoshi Okada, Jennifer Liepa, Andrew Wakeham, Kathrin Zaugg, and Tak W. Mak* Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Suite 706, Toronto, ON, Canada M5G 2C1; and Department of Medical Biophysics and Immunology, University of Toronto, Toronto, ON, Canada M5G 2C1 Contributed by Tak W. Mak, August 25, 2004 FKHRL1 (FOXO3a) and p53 are two potent stress-response regula- transcription factors communicate and coordinate with each tors. Here we show that these two transcription factors exhibit other in controlling cell fate in response to genotoxic stress. ‘‘crosstalk’’ in vivo. In response to DNA damage, p53 activation led to FKHRL1 phosphorylation and subcellular localization change, Experimental Procedures which resulted in inhibition of FKHRL1 transcription activity. AKT Cell Culture. E1A͞H-ras-V12-transformed p53ϩ͞ϩ and p53Ϫ͞Ϫ was dispensable for p53-dependent suppression of FKHRL1. By mouse embryonic fibroblasts (MEFs) were kind gifts from Scott contrast, serum- and glucocorticoid-inducible kinase 1 (SGK1) was Lowe (Cold Spring Harbor Laboratory, Cold Spring Harbor, significantly induced in a p53-dependent manner after DNA dam- NY). p53QS primary MEFs were a gift of Geoffrey Wahl (The age, and this induction was through extracellular signal-regulated Salk Institute for Biological Studies, San Diego). MEFs were kinase 1͞2-mediated posttranslational regulation. Furthermore, cultured in DMEM (GIBCO) supplemented with 10% FCS inhibition of SGK1 expression by a small interfering RNA knock- (GIBCO). Primary MEFs were transformed with pLPC ras͞E1A down experiment significantly decreased FKHRL1 phosphorylation (a gift from Athena Lin, Roswell Park Cancer Institute, Buffalo, in response to DNA damage. Taken together, our observations NY) and then subjected to puromycin selection. Pharmacolog- reveal previously unrecognized crosstalk between p53 and ical inhibitors PD98059 (50 ␮M), LY294002 (10 ␮M), and FKHRL1. Moreover, our findings suggest a new pathway for SB203580 (20 ␮M) were purchased from Calbiochem. understanding aging and the age dependency of human diseases governed by these two transcription factors. Constructs and Antibodies. The pSIRIPP retroviral small interfer- ing RNA (siRNA) vector (a gift from Tyler Jacks, Massachusetts Institute of Technology, Cambridge) is described in ref. 16. uman longevity depends on genome stability. Several Oligonucleotide sequences for murine serum- and glucocorti- mouse models have revealed that an age-related decrease of H coid-inducible kinase 1 (SGK1) siRNA are available on request. DNA repair or an increase in DNA damage plays a role in The pBabe Akt-KD, human WT p53, p53R175H, and p53R273H mammalian aging (1–3). The idea that cellular responses to stress expression plasmids were kindly provided by Arnold Levine may be important in aging is supported by studies of p53, the (Institute for Advanced Study, Princeton). pECE-HA- functions of which are critical for both the apoptotic and FKHRL1, HA-FKHRL1-TM expression plasmids, and the anti- senescence responses to DNA damage, telomeric shortening, SGK antibody were generously provided by Michael Greenberg and oxidative stress (4–6). (Harvard Medical School, Boston). Anti-p53 antibody (FL393, The mammalian FOXO family of forkhead transcription Santa Cruz Biotechnology), anti-p21 and anti-p27 antibodies factors (including FKHR, FKHRL1, and AFX) have been (BD Biosciences), antibodies against total FKHRL1 or phospho- proposed as antiaging factors based on evidence from their Thr-32 FKHRL1 (Upstate Biotechnology, Lake Placid, NY), orthologues, DAF-16 in Caenorhabditis elegans and dFOXO in anti-total-Akt or phospho-Akt antibodies (Cell Signaling Tech- Drosophila melanogaster, which regulate longevity in response to ͞ nology, Beverly, MA), and anti-total-extracellular signal- reduced insulin insulin-like growth factor I (IGF-I) signaling or regulated kinase (ERK) 1͞2 or phospho-ERK1͞2 antibodies by overexpressing constitutively active FOXO (7, 8). Growth (Cell Signaling Technology) were purchased commercially. factor signaling to FOXO family members through phosphati- dylinositol 3-kinase (PI3K) and its downstream kinase, Akt, has Retroviral Infection. Phoenix cells were transfected with indicated been found to be evolutionarily conserved for FOXO phosphor- retroviral constructs by calcium chloride transfection. At 24 h ylation, subcellular translocation, and inhibition of its transcrip- posttransfection, conditioned medium recovered from cultures tional activity (9). However, the role of FOXO in response to of transfected Phoenix cells was filtered through a 0.45-␮m filter DNA damage, as well as the signaling pathway upstream of and added to the MEF cultures. Spin infection was performed at FOXO, is, as yet, unclear. Overexpression of FKHRL1 can 1,400 ϫ g for 90 min. Cells were then cultured for Ϸ20 h and then protect cells from oxidative stress-induced cell death, as de- subjected to puromycin selection. scribed in refs. 10–12. Induction of a number of antioxidant enzymes and stress-related gene products has been proposed as Chromatin Immunoprecipitation (ChIP) Assays. ChIP assays were a potential mechanism (9, 13–15). The fact that the precise performed by using an Acetyl-Histone H3 Immunoprecipitation biological consequences of FOXO activation are cell-type- 7 Assay Kit (17-245, Upstate Biotechnology). Briefly, 10 cells BIOCHEMISTRY specific and stress-type-dependent suggests that there might be were fixed with 1% formaldehyde and then washed, harvested in crosstalk between FOXO and other stress regulators. How FOXO communicates and coordinates with other signaling pathways in response to genotoxic stress remains unknown. Abbreviations: Akt-DN, kinase-dead form of Akt; ChIP, chromatin immunoprecipitation; CISK, cytokine-independent survival kinase; ERK, extracellular signal-regulated kinase, The opposing functions of p53 and FKHRL1 with regard to IGF-I, insulin-like growth factor I; MEF, mouse embryonic fibroblast; PI3K, phosphatidyl- the aging process suggest that a regulatory mechanism might inositol 3-kinase; SGK1, serum- and glucocorticoid-inducible kinase 1; siRNA, small inter- exist to integrate these two signaling pathways. We sought to fering RNA; TNF-␣, tumor necrosis factor ␣. elucidate the mechanism underlying this crosstalk and its regu- *To whom correspondence should be addressed. E-mail: [email protected]. lation in the hopes of better understanding how these two © 2004 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0406286101 PNAS ͉ September 28, 2004 ͉ vol. 101 ͉ no. 39 ͉ 14057–14062 Downloaded by guest on September 29, 2021 Fig. 1. p53 negatively regulates FKHRL1 in response to genotoxic stress. (A) Increased phosphorylation of FKHRL1 after DNA damage in the presence of p53. Transformed WT and p53Ϫ͞Ϫ MEFs were treated with UV radiation (30 J͞m2), etoposide (0.5 ␮M), or TNF-␣ (10 ng͞ml). Cell extracts were analyzed at the indicated time points by immunoblotting with antibodies directed against p53, p21, and phosphorylated FKHRL1. Actin was used as the loading control. For all figures, results shown are representative of at least three independent experiments. (B) p53-dependent and -independent apoptosis and G2͞M arrest caused by various stimuli. Transformed WT and p53Ϫ͞Ϫ MEFs were treated for 24 h with the same DNA-damaging agents as in A, followed by propidium iodide (PI) staining and fluorescence-activated cell sorter analysis. Data are shown for the sub-G1 (apoptosis) (Left) and G2–M(Right) phases. Data are the means and variances for two independent experiments performed in duplicate. (C) Nuclear exclusion of FKHRL1 induced by p53 in response to DNA damage. p53Ϫ͞Ϫ MEFs were cotransfected with an expression plasmid encoding HA-tagged WT FKHRL1 plus a plasmid encoding WT p53, p53R175H, or p53R273H. At 24 h posttransfection, cells were treated with UV radiation (30 J͞m2) for 8 h. FKHRL1 was detected by immunofluorescent staining with anti-HA antibody. Nuclear DNA was stained with 4Ј,6-diamidino-2-phenylindole. The images were merged to detect nuclear localization͞exclusion of FKHRL1. Results shown are one trial representative of three experiments. Quantification of the means and variances from three experiments is shown. (D) Decreased p27 expression in WT cells after DNA damage treatment. WT and p53Ϫ͞Ϫ MEFs were exposed to UV radiation (30 J͞m2) for 10 h or etoposide (0.5 ␮M) for 5 or 10 h. Cell lysates were analyzed by Western blotting with antibodies against p27 and actin. (E) Reduced association of FKHRL1 with the endogenous p27 and cyclin G2 promoters in the presence of p53 upon UV radiation. ChIP assays were performed on WT or p53Ϫ͞Ϫ MEFs left untreated or treated with UV radiation (30 J͞m2) for 10 h. PCR was conducted by using primers flanking murine p27 or cyclin G2 promoter regions containing FKHRL1-binding motifs. DNA templates from a protein–DNA complex immunoprecipitated with either FKHRL1-specific antibody (Upper) or no antibody (Lower, ϪAb) were used. Input DNA was amplified for normalization (Lower). SDS lysis buffer, and sonicated. Lysates containing soluble with phenol͞chloroform and precipitated with ethanol. Murine chromatin were prepared and incubated overnight with 2.5 ␮g p27 ChIP primer sequences are available on request. Cyclin G2 of anti-FKHR antibody (H-144, Santa Cruz Biotechnology). primers
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