Activation of AMP-activated Protein Kinase Induces p53-dependent Apoptotic Cell Death in Response to Energetic Stress

Abstract

Tumor suppressor p53-dependent stress response pathways play an important role in cell fate determination. In this study, we have found that glucose depletion promotes the phosphorylation of AMP-activated protein kinase catalytic subunit α (AMPKα) in association with a significant up-regulation of p53, thereby inducing p53-dependent apoptosis in vivo and in vitro. Thymocytes prepared from glucose-depleted wild-type mice but not from p53-deficient mice underwent apoptosis, which was accompanied by a remarkable phosphorylation of AMPKα and a significant induction of p53 as well as pro-apoptotic Bax. Similar results were also obtained in human osteosarcoma-derived U2OS cells bearing wild-type p53 following glucose starvation. Of note, glucose deprivation led to a significant accumulation of p53 phosphorylated at Ser-46, but not at Ser-15 and Ser-20, and a transcriptional induction of p53 as well as proapoptotic p53 AIP1. Small interference RNA-mediated knockdown of p53 caused an inhibition of apoptosis following glucose depletion. Additionally, apoptosis triggered by glucose deprivation was markedly impaired by small interference RNA-mediated depletion of AMPKα. Under our experimental conditions, down-regulation of AMPKα caused an attenuation of p53 accumulation and its phosphorylation at Ser-46. In support of these observations, enforced expression of AMPKα led to apoptosis and resulted in an induction of p53 at protein and mRNA levels. Furthermore, p53 promoter region responded to AMPKα and glucose deprivation as judged by luciferase reporter assay. Taken together, our present findings suggest that AMPK-dependent transcriptional induction and phosphorylation of p53 at Ser-46 play a crucial role in the induction of apoptosis under carbon source depletion. Tumor suppressor p53-dependent stress response pathways play an important role in cell fate determination. In this study, we have found that glucose depletion promotes the phosphorylation of AMP-activated protein kinase catalytic subunit α (AMPKα) in association with a significant up-regulation of p53, thereby inducing p53-dependent apoptosis in vivo and in vitro. Thymocytes prepared from glucose-depleted wild-type mice but not from p53-deficient mice underwent apoptosis, which was accompanied by a remarkable phosphorylation of AMPKα and a significant induction of p53 as well as pro-apoptotic Bax. Similar results were also obtained in human osteosarcoma-derived U2OS cells bearing wild-type p53 following glucose starvation. Of note, glucose deprivation led to a significant accumulation of p53 phosphorylated at Ser-46, but not at Ser-15 and Ser-20, and a transcriptional induction of p53 as well as proapoptotic p53 AIP1. Small interference RNA-mediated knockdown of p53 caused an inhibition of apoptosis following glucose depletion. Additionally, apoptosis triggered by glucose deprivation was markedly impaired by small interference RNA-mediated depletion of AMPKα. Under our experimental conditions, down-regulation of AMPKα caused an attenuation of p53 accumulation and its phosphorylation at Ser-46. In support of these observations, enforced expression of AMPKα led to apoptosis and resulted in an induction of p53 at protein and mRNA levels. Furthermore, p53 promoter region responded to AMPKα and glucose deprivation as judged by luciferase reporter assay. Taken together, our present findings suggest that AMPK-dependent transcriptional induction and phosphorylation of p53 at Ser-46 play a crucial role in the induction of apoptosis under carbon source depletion. AMP-activated protein kinase (AMPK) 3The abbreviations used are: AMPKAMP-activated protein kinaseDAPI4,6-diamidino-2-phenylindoleFACSfluorescence-activated cell sorterFBSfetal bovine serumGAPDHglyderaldehyde-3-phosphate dehydrogenaseIBimmunoblottingPARPpoly(ADP-ribose) polymerasePBSphosphate-buffered salineRTreverse transcriptionsiRNAsmall interference RNA. was originally identified as an enzyme that has an ability to inhibit hydroxymethylglutaryl-CoA reductase (1Beg G.H. Allmann D.W. Gibson D.M. Biochem. Biophys. Res. Commun. 1973; 54: 1362-1369Crossref PubMed Scopus (219) Google Scholar) and also regulate acetyl-CoA carboxylase by reversible phosphorylation (2Carlson C.A. Kim K.H. J. Biol. Chem. 1973; 248: 378-380Abstract Full Text PDF PubMed Google Scholar). Subsequent studies demonstrated that AMPK is widely expressed and exists as a heterotrimeric complex, which consists of a catalytic subunit (α) and two regulatory subunits (β and γ). The mammalian genome contains seven AMPK genes encoding two α (α1 and α2), two β (β1 and β2), and three γ (γ1, γ2, and γ3) isoforms (3Rutter G.A. Da Silva Xavier G. Leclerc I. Biochem. J. 2003; 375: 1-16Crossref PubMed Scopus (287) Google Scholar, 4Carling D. Trends Biochem. Sci. 2004; 29: 18-24Abstract Full Text Full Text PDF PubMed Scopus (963) Google Scholar, 5Hardie D.G. J. Cell Sci. 2004; 117: 5479-5487Crossref PubMed Scopus (965) Google Scholar). The catalytic α subunit is composed of three functional domains, including an NH2-terminal Ser/Thr protein kinase domain, a central auto-inhibitory region, and a COOH-terminal regulatory subunit-binding domain. AMPK acts as an intracellular energy sensor by monitoring cellular energy levels. For example, AMPK becomes activated by the tumor suppressor LKB1 complex-mediated phosphorylation at Thr-172 in response to certain energy-depleting stresses such as glucose deprivation, hypoxia, and oxidative stress, which increase the intracellular AMP:ATP ratio (6Hardie D.G. Endocrinology. 2003; 144: 5179-5183Crossref PubMed Scopus (841) Google Scholar, 7Xing Y. Musi N. Fujii N. Zou L. Luptak I. Hirshman M.F. Goodyear L.J. Tian R. J. Biol. Chem. 2003; 278: 28372-28377Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 8Hawley S.A. Boudeau J. Reid J.L. Mustard K.J. Udd L. Makela T.P. Allesi D.R. Hardie D.G. J. Biol. 2003; 2: 28Crossref PubMed Google Scholar, 9Woods A. Johnstone S.R. Dickerson K. Leiper F.C. Fryer L.G. Neumann D. Schlattner U. Wallimann T. Carlson M. Carling D. Curr. Biol. 2003; 13: 2004-2008Abstract Full Text Full Text PDF PubMed Scopus (1352) Google Scholar, 10Shaw R.J. Bardeesy N. Manning B.D. Lopez L. Kosmatka M. De-Pinho R.A. Cantley L.C. Cancer Cell. 2004; 6: 91-99Abstract Full Text Full Text PDF PubMed Scopus (886) Google Scholar). AMPK can also be activated allosterically in the AMP:ATP ratio (11Hardie D.G. Carling D. Carlson M. Annu. Rev. Biochem. 1998; 67: 821-855Crossref PubMed Scopus (1281) Google Scholar). Upon activation, AMPK down-regulates the ATP consuming metabolic pathways and activates the energy-generating processes through phosphorylating the primary targets involved in energy metabolism, thereby maintaining energy balance within cells (4Carling D. Trends Biochem. Sci. 2004; 29: 18-24Abstract Full Text Full Text PDF PubMed Scopus (963) Google Scholar). AMP-activated protein kinase 4,6-diamidino-2-phenylindole fluorescence-activated cell sorter fetal bovine serum glyderaldehyde-3-phosphate dehydrogenase immunoblotting poly(ADP-ribose) polymerase phosphate-buffered saline reverse transcription small interference RNA. Pro-apoptotic p53 is a founding member of the p53 tumor suppressor family and acts as a critical regulator of many cellular processes such as cell cycle arrest and apoptosis (12Vogelstein B. Lane D. Levine A.J. Nature. 2000; 408: 307-310Crossref PubMed Scopus (5850) Google Scholar). p53 is frequently mutated in over 50% of human tumors (13Caron de Fromentel C. Soussi T. Genes Chromosomes Cancer. 1992; 4: 1-15Crossref PubMed Scopus (536) Google Scholar, 14Greenblatt M.S. Bennett W.P. Hollstein M. Harris C.C. Cancer Res. 1994; 54: 4855-4878PubMed Google Scholar, 15Chao C. Hergenhahn M. Kaeser M.D. Wu Z. Saito S. Iggo R. Hollstein M. Appella E. Xu Y. J. Biol. Chem. 2003; 278: 41028-41033Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar), and p53-deficient mice developed spontaneous tumors (16Donehower L.A. Harvey M. Slagle B.L. McArthur M.J. Montgomery Jr., C.A. Butel J.S. Bradley A. Nature. 1992; 356: 215-221Crossref PubMed Scopus (4054) Google Scholar). p53 acts as a nuclear sequence-specific transcription factor and transactivates its numerous target genes implicated in cell cycle arrest and apoptotic cell death, including p21WAF1, Bax, Puma, Noxa, and p53 AIP1. Its pro-apoptotic function is closely linked to its DNA binding activity. Indeed, over 90% of the p53 mutation is detected within its sequence-specific DNA-binding domain (13Caron de Fromentel C. Soussi T. Genes Chromosomes Cancer. 1992; 4: 1-15Crossref PubMed Scopus (536) Google Scholar, 14Greenblatt M.S. Bennett W.P. Hollstein M. Harris C.C. Cancer Res. 1994; 54: 4855-4878PubMed Google Scholar, 15Chao C. Hergenhahn M. Kaeser M.D. Wu Z. Saito S. Iggo R. Hollstein M. Appella E. Xu Y. J. Biol. Chem. 2003; 278: 41028-41033Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Intracellular p53 protein levels are tightly regulated predominantly through the ubiquitin-proteasome protein degradation pathway. MDM2, which interacts with the NH2-terminal transactivation domain of p53 and inhibits its transcriptional activity, is one of the ubiquitin-protein isopeptide ligases for p53 (17Haupt Y. Maya R. Kazaz A. Oren M. Nature. 1997; 387: 296-299Crossref PubMed Scopus (3750) Google Scholar, 18Kubbutat M.H. Jones S.N. Vousden K. Nature. 1997; 387: 299-303Crossref PubMed Scopus (2860) Google Scholar). In response to various types of cellular stress, including DNA damage, hypoxia, nucleotide pool reduction, and thermal shock, p53 is induced to be stabilized as well as activated in the cell nucleus, and thereby plays a key role in the regulation of cell fate determination (19Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1234) Google Scholar, 20Sionov R.V. Haupt Y. Oncogene. 1999; 18: 6145-6157Crossref PubMed Scopus (503) Google Scholar, 21Vousden K.H. Lu X. Rev. Cancer. 2: PubMed Scopus Google Scholar). has that cells with glucose arrest in the of the cell cycle in association with a significant of AMPK D.R. S. M. J. Xu Y. M.J. Cell. 18: Full Text Full Text PDF PubMed Scopus Google Scholar). to cell cycle arrest in response to glucose the phosphorylation of tumor suppressor p53 at phosphorylation of p53 at which the its as well as (19Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1234) Google Scholar, 20Sionov R.V. Haupt Y. Oncogene. 1999; 18: 6145-6157Crossref PubMed Scopus (503) Google Scholar, 21Vousden K.H. Lu X. Rev. Cancer. 2: PubMed Scopus Google Scholar), is that p53 plays an important role in the regulation of cell cycle arrest caused by glucose Indeed, p53-deficient cells to arrest under glucose D.R. S. M. J. Xu Y. M.J. Cell. 18: Full Text Full Text PDF PubMed Scopus Google Scholar). with these of AMPK in human cells bearing wild-type p53 resulted in cell cycle arrest through of p53 K. T. A. M. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar). C. I. C. C. Biochem. Biophys. Res. Commun. 1998; PubMed Scopus Google Scholar) that AMPK has a role apoptosis in response to In this study, we have found that glucose deprivation phosphorylation of AMPKα and promotes p53-dependent apoptotic cell in vivo and in vitro. Under our experimental conditions, p53 was induced in response to glucose depletion at mRNA and at protein levels. present findings suggest that AMPK acts as a metabolic sensor to cell fate through the of pro-apoptotic mice which were from were in an a cycle at a of and to and For was from the at the of the cycle for the to was with these mice were with the of the Cancer and Cell and osteosarcoma-derived U2OS cells were in with fetal bovine serum and cells were in with cells were in a of at U2OS cells were in with For U2OS and cells were with the of the expression to the was used as a to balance the of DNA in and was prepared from the cells by the to the and with reverse The was by with DNA polymerase the following p53, and p21WAF1, and Bax, and p53 and and and and and The expression of was as an were the and the The cells were in a and for and to a for at by at at for to The protein were the protein to the The of protein were by and The were with saline and at the were with at Ser-15 at at Ser-46 with R.V. Haupt Y. Oncogene. 1999; 18: 6145-6157Crossref PubMed Scopus (503) Google Scholar, 21Vousden K.H. Lu X. Rev. Cancer. 2: PubMed Scopus Google Scholar, D.R. S. M. J. Xu Y. M.J. Cell. 18: Full Text Full Text PDF PubMed Scopus Google Scholar, K. T. A. M. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar, C. I. C. C. Biochem. Biophys. Res. Commun. 1998; PubMed Scopus Google Scholar, K. T. K. C. T. K. T. Y. Y. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, K. K. Y. K. Y. Cancer Res. Google Scholar, D.R. Cell. Biol. 2003; PubMed Scopus Google Scholar, A. Y. Cell Biol. 4: PubMed Scopus (503) Google Scholar, G. B. T. I. Y. Saito S. M. S. A. G. G. M. Appella E. S. Cell Biol. 4: PubMed Scopus Google Scholar, I. J. Cancer Res. 67: PubMed Scopus Google Scholar, K. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Levine A.J. Nature. PubMed Scopus Google Scholar, A. Y. Y. Oncogene. 2000; PubMed Scopus Google for at with primary the were with for at were by to the the glucose cell prepared from U2OS cells were with of protein for at and were with the at the were with of protein and for at The were with and by by immunoblotting with the cells were in the of the glucose deprivation, cells were in for at in for at and with bovine serum in phosphate-buffered saline for at cells were in and with and with and for at by the with and for at Cell were with The was by a glucose deprivation, and cells were by and in The cells were with of and with of for at the DNA by was by cells were in at a of and with a of a luciferase reporter by the p53 promoter and of luciferase expression with the of the expression for AMPK For the DNA were cells were and luciferase were by luciferase reporter an luciferase to luciferase was at three by of the for and the expression for and we prepared from U2OS cells as a For the of the region was by the following and which and The of the region was also by the following and which and The and of the were with and with and and and of to For the of the region was by the following and which and The of the region was also by the following and which and The to of the region were with and with and and and of to of the were to the of the U2OS cells were with of the and with the to the and cell were prepared used in the present are Cell in and in glucose depletion apoptotic cell in we have prepared from wild-type and p53-deficient mice that were in the of glucose for and cell cycle were by in glucose deprivation resulted in a significant increase in of with DNA in wild-type glucose depletion from p53-deficient that glucose apoptotic cell be regulated in a p53-dependent with the D.R. S. M. J. Xu Y. M.J. Cell. 18: Full Text Full Text PDF PubMed Scopus Google Scholar), glucose depletion the phosphorylation of AMPKα in wild-type Under our experimental conditions, p53 in response to glucose starvation. the accumulation of p53 was with a significant induction of AMPKα phosphorylation as well as pro-apoptotic Bax, which is one of the targets of p53 (19Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1234) Google Scholar, 20Sionov R.V. Haupt Y. Oncogene. 1999; 18: 6145-6157Crossref PubMed Scopus (503) Google Scholar, 21Vousden K.H. Lu X. Rev. Cancer. 2: PubMed Scopus Google Scholar). Additionally, of which is one of the of the activated was induced in response to glucose In the expression levels of p21WAF1, which have to be implicated in p53-dependent cell cycle arrest (19Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1234) Google Scholar, 20Sionov R.V. Haupt Y. Oncogene. 1999; 18: 6145-6157Crossref PubMed Scopus (503) Google Scholar, 21Vousden K.H. Lu X. Rev. Cancer. 2: PubMed Scopus Google Scholar), of glucose this in human osteosarcoma-derived U2OS cells bearing wild-type p53 were in in glucose for the and we cell cycle by in glucose depletion led to a apoptotic cell that the expression levels of and p53 was induced of which was with the up-regulation of pro-apoptotic and p53 K. T. K. C. T. K. T. Y. Y. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, K. K. Y. K. Y. Cancer Res. Google Scholar), the expression levels of the glucose apoptotic cell demonstrated that AMPKα is induced to be phosphorylated following glucose In of AMPKα in the of Additionally, glucose deprivation led to an accumulation of p53 as well as an induction of p53 phosphorylation at Ser-46 but not at Ser-15 and the expression levels of pro-apoptotic but not of and of was in response to glucose of p53 Cell p53 be involved in apoptotic cell in response to glucose U2OS cells were with with cells were the glucose cell were prepared and for the expression levels of p53 by in p53 was induced to in cells with the of p53 were at levels in cells with that knockdown of p53 the of cells with DNA in response to glucose deprivation as with that of cells p53-deficient human osteosarcoma-derived cells underwent apoptotic cell in response to glucose deprivation to a that p53 at in to the induction of apoptotic cell following glucose depletion. glucose deprivation resulted in the induction of AMPKα we the of AMPKα glucose apoptotic cell this knockdown of and was cells were in the of the glucose cells were and cell cycle were by in knockdown apoptotic cell caused by glucose to demonstrated that knockdown of and not the phosphorylation of AMPKα as well as the accumulation of p53 in response to glucose deprivation induction of p53 phosphorylation at Ser-46 was not in cells and were Additionally, that knockdown of and inhibits the transcriptional up-regulation of p53 as well as p53 Under our experimental conditions, these results suggest that AMPKα the glucose apoptotic cell through the induction of p53 at mRNA and protein levels. AMPKα an to that p53 is stabilized at a protein in response to a of cellular stresses (19Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1234) Google Scholar, 20Sionov R.V. Haupt Y. Oncogene. 1999; 18: 6145-6157Crossref PubMed Scopus (503) Google Scholar, 21Vousden K.H. Lu X. Rev. Cancer. 2: PubMed Scopus Google Scholar), our present results suggest that of AMPKα the transcriptional of the p53 promoter to we have a luciferase reporter a region that nucleotide from to to the transcriptional of the human p53 of U2OS cells were with the of and with the of the expression for and cells were and luciferase were in of expression of and the luciferase by p53 promoter in a Furthermore, luciferase by the p53 promoter were in response to glucose of results were with our present that p53 is regulated at in at a transcriptional following glucose depletion. the the transcriptional of p53 promoter studies are to this AMPKα and p53 in we AMPKα with p53 in For this we the the glucose deprivation, U2OS cells were with and Cell were with that p53 with within the cell nucleus, and are in response to glucose deprivation of with which is one of the for of is that p53 with in Under our experimental conditions, significant were in the of and glucose accumulation of in was not in cells with AMPKα the of p53 with we U2OS cells were in the of the glucose cell were prepared and with by immunoblotting with with Under our experimental conditions, and AMPKα were not with in the and that p53 be with phosphorylated and of AMPKα. in that the but not is with the p53 of AMPKα Cell in with the of AMPKα apoptotic cell through the induction of p53, U2OS cells were with the of the expression for and cells were and cell cycle were by in cells underwent apoptotic cell in a demonstrated that the expressed AMPKα is phosphorylated in a levels of p53 and its phosphorylation at Ser-46 were in the of expressed and with our present enforced expression of and resulted in the transcriptional up-regulation of p53 as well as pro-apoptotic p53 In expression of and led to an induction of p53 and p53 in a Taken together, our present findings suggest that induction of p53 plays an important role in the regulation of cell fate determination in response to glucose has under glucose conditions, AMPK-dependent of tumor suppressor p53 cell cycle that p53 as a metabolic sensor in response to glucose D.R. S. M. J. Xu Y. M.J. Cell. 18: Full Text Full Text PDF PubMed Scopus Google Scholar). to AMPK-dependent phosphorylation of p53 at Ser-15 plays an role in the of activated AMPK p53-dependent cell cycle In glucose depletion led to apoptotic cell through the of pro-apoptotic D.R. Cell. Biol. 2003; PubMed Scopus Google Scholar). In this study, we have found that glucose deprivation the phosphorylation of AMPKα and p53-dependent apoptotic cell in vivo and in vitro. glucose apoptotic cell was with a significant transcriptional up-regulation of p53 and induction of p53 phosphorylation at Ser-46. In response to various cellular stresses such as DNA damage, p53 is phosphorylated at including Ser-20, and Ser-46 K.H. Lu X. Rev. Cancer. 2: PubMed Scopus Google Scholar). of cell cycle arrest and apoptotic cell has to be the important of p53 in cells to various cellular stresses (19Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1234) Google Scholar, 20Sionov R.V. Haupt Y. Oncogene. 1999; 18: 6145-6157Crossref PubMed Scopus (503) Google Scholar, 21Vousden K.H. Lu X. Rev. Cancer. 2: PubMed Scopus Google the for the p53-dependent cell cycle arrest and apoptotic cell in response to cellular stresses have K. T. K. C. T. K. T. Y. Y. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) found an important to this to p53 was phosphorylated at Ser-46 following DNA damage, and thereby cells with DNA underwent apoptotic cell DNA phosphorylation of p53 at Ser-46 the p53-dependent apoptotic by proapoptotic p53 AIP1. p53 which is in is one of transcriptional targets of p53 and has an ability to and thereby from the to the K. T. K. C. T. K. T. Y. Y. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, K. K. Y. K. Y. Cancer Res. Google Scholar). is that the phosphorylation of p53 at Ser-46 is one of the critical for of cell fate apoptotic cell our present metabolic stress by glucose deprivation apoptotic cell in association with a significant phosphorylation of AMPKα as well as p53 at Ser-46 but not at Ser-15 and phosphorylation of p53 at Ser-46 was with the transcriptional up-regulation of pro-apoptotic and p53 AIP1. In support of these knockdown of the AMPKα markedly the glucose apoptotic cell and phosphorylation of p53 at Ser-46 as well as the transcriptional up-regulation of p53 AIP1. Indeed, enforced expression of AMPKα apoptotic cell and p53 phosphorylation at Ser-46 in association with the transcriptional of p53 AIP1. our present results suggest that the of the AMPK is for the metabolic phosphorylation of p53 at Ser-46, thereby inducing apoptotic cell A. Y. Cell Biol. 4: PubMed Scopus (503) Google Scholar, G. B. T. I. Y. Saito S. M. S. A. G. G. M. Appella E. S. Cell Biol. 4: PubMed Scopus Google Scholar, I. J. Cancer Res. 67: PubMed Scopus Google Scholar), protein with p53 and p53 phosphorylation at Ser-46. In to K. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) found that protein kinase phosphorylation of p53 at Ser-46 in response to stress, that protein kinase is a for Ser-46 of this was that glucose accumulation of p53 be at in to the transcriptional up-regulation of p53, and AMPK play an important role in the transcriptional regulation of that p53 is induced to through the such as phosphorylation and in response to a of cellular stresses (19Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1234) Google Scholar, 20Sionov R.V. Haupt Y. Oncogene. 1999; 18: 6145-6157Crossref PubMed Scopus (503) Google Scholar, 21Vousden K.H. Lu X. Rev. Cancer. 2: PubMed Scopus Google Scholar). the the regulatory of p53 transcription have and Levine Levine A.J. Nature. PubMed Scopus Google Scholar) that p53 is regulated in response to as well as serum starvation. A. Y. Y. Oncogene. 2000; PubMed Scopus Google Scholar) identified the promoter at a nucleotide from to to the transcriptional within the p53 promoter region for p53 expression and In has that protein has an ability to the p53 S.A. D. E. E. J. S. Nature. 2000; PubMed Scopus Google Scholar, A. M. K. D. S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is that exists a within the p53 promoter region, thereby a p53 expression S. Cancer Res. PubMed Scopus Google Scholar). to our present knockdown of the AMPKα the transcriptional induction of p53 in response to glucose with these observations, glucose depletion the promoter of p53 as by luciferase reporter Furthermore, enforced expression of AMPKα resulted in a increase in luciferase by the p53 promoter in the of metabolic the AMPK is involved in the regulation of expression D.G. J. Cell Sci. 2004; 117: 5479-5487Crossref PubMed Scopus (965) Google Scholar), is that the activated of AMPK the transcription of p53 through as studies are to this that p53 is with and phosphorylated of AMPKα glucose that glucose phosphorylation of AMPKα is with the up-regulation of p53, is that phosphorylated of AMPKα to glucose induction of p53 through the with demonstrated glucose phosphorylated of AMPKα with p53 within the a that is a of S.N. L. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In to the of has that the be involved in numerous cellular including cell cycle DNA and K. M. A. L. S. J. Cell Biol. PubMed Scopus Google Scholar). A. A. K. M. R. M. A. C. Oncogene. PubMed Scopus Google Scholar) that nuclear and the COOH-terminal region of p53 are for its the functional of the of p53 are J. D. M. J. Cancer. PubMed Scopus Google Scholar) that the of p53 to its in response to stress caused by is that the an important for p53 function under to our in but not was with AMPK is a heterotrimeric protein kinase of and γ In mammalian subunit exists in which to heterotrimeric has that two wild-type AMPK catalytic and response to M. U. R. Schlattner U. Wallimann T. Neumann D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). our present is that AMPK have a role in the regulation of apoptotic cell through the functional with p53, are to this Y. for with