c-Myc Sensitization to Oxygen Deprivation-induced Cell Death Is Dependent on Bax/Bak, but Is Independent of p53 and Hypoxia-inducible Factor-1

Deregulated expression of c-Myc can sensitize cells to a variety of death stimuli, including loss of growth factors and oxygen. In this study, we examined whether rodent fibroblasts that conditionally express c-Myc undergo a similar mechanism of cell death in response to serum or oxygen deprivation. Our results demonstrate that murine embryonic fibroblasts from bax-/-bak-/- mice that conditionally express c-Myc did not die in response to either oxygen or serum deprivation. Fibroblasts from p53-/- mice that conditionally express c-Myc died in response to oxygen (but not serum) deprivation. The inability of p53 to regulate oxygen deprivation-induced cell death was due to the lack of induction of p53 target genes Puma, Noxa, and Pten. In contrast, serum deprivation transcriptionally induced Puma and Pten in cells that conditionally express c-Myc. The failure of p53 to regulate oxygen deprivation-induced cell death led us to hypothesize whether hypoxia-inducible factor (HIF) might be a critical regulator of cell death during oxygen deprivation. Fibroblasts from HIF-1β-/- cells that conditionally express c-Myc were not able to transcriptionally activate HIF during oxygen deprivation. These cells died in response to oxygen deprivation. Thus, oxygen deprivation-induced cell death in fibroblasts with deregulated expression of c-Myc is independent of p53 or HIF-1 status, but is dependent on the Bcl-2 family member Bax or Bak to initiate mitochondrial dependent cell death. Deregulated expression of c-Myc can sensitize cells to a variety of death stimuli, including loss of growth factors and oxygen. In this study, we examined whether rodent fibroblasts that conditionally express c-Myc undergo a similar mechanism of cell death in response to serum or oxygen deprivation. Our results demonstrate that murine embryonic fibroblasts from bax-/-bak-/- mice that conditionally express c-Myc did not die in response to either oxygen or serum deprivation. Fibroblasts from p53-/- mice that conditionally express c-Myc died in response to oxygen (but not serum) deprivation. The inability of p53 to regulate oxygen deprivation-induced cell death was due to the lack of induction of p53 target genes Puma, Noxa, and Pten. In contrast, serum deprivation transcriptionally induced Puma and Pten in cells that conditionally express c-Myc. The failure of p53 to regulate oxygen deprivation-induced cell death led us to hypothesize whether hypoxia-inducible factor (HIF) might be a critical regulator of cell death during oxygen deprivation. Fibroblasts from HIF-1β-/- cells that conditionally express c-Myc were not able to transcriptionally activate HIF during oxygen deprivation. These cells died in response to oxygen deprivation. Thus, oxygen deprivation-induced cell death in fibroblasts with deregulated expression of c-Myc is independent of p53 or HIF-1 status, but is dependent on the Bcl-2 family member Bax or Bak to initiate mitochondrial dependent cell death. The proto-oncogene c-Myc is a transcription factor that forms a heterodimer with Max and activates genes involved in proliferation (1Amati B. Brooks M.W. Levy N. Littlewood T.D. Evan G.I. Land H. Cell. 1993; 72: 233-245Abstract Full Text PDF PubMed Scopus (444) Google Scholar). However, cells expressing c-Myc rapidly undergo cell death under conditions in which survival factors are limiting (reviewed in Ref. 2Prendergast G.C. Oncogene. 1999; 18: 2967-2987Crossref PubMed Scopus (391) Google Scholar). The molecular machinery that regulates c-Myc-induced cell death is distinct and independent from proliferation because activation of the molecular machinery mediating cell cycle progression is not required for c-Myc-induced cell death (3Conzen S.D. 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Biol. 2001; PubMed Scopus Google Scholar). whether Bax or Bak is required for oxygen or serum deprivation-induced cell death in cells the c-Myc was in from and and were with for and of either serum or oxygen for The cells with were from both serum and oxygen deprivation-induced cell death These results that both serum and oxygen deprivation-induced cell death pathways on Bax or Bak to cause outer mitochondrial membrane or bax-/-bak-/- fibroblasts that express a c-Myc were under oxygen conditions with in the of for cell death was in cells of either oxygen or serum for are as from independent c and the of p53 and Bcl-xL in cell death by cytochrome c release and release cytochrome c in the of cell death due to loss of outer mitochondrial membrane c in the cytosol to which a that the and activation of P. D. I. M. E.S. Wang X. Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar, X. Kim C.N. J. R. Wang X. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, H. 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The loss of p53 serum deprivation-induced cell death in fibroblasts conditionally expressing c-Myc at a of cytochrome c release and to p53 Genes in with Deregulated c-Myc p53 is required under conditions of serum (but not we examined p53 and p53 transcriptionally genes Puma, Noxa, and Pten in in the of either serum or oxygen. Puma and are proteins that can activate Bax or Bak and have been in p53-dependent cell death X. Nat. 2002; PubMed Scopus Google Scholar). Pten is a regulator of the survival and has been shown to be required for cell death in V. D. D. Y. B. Y. S. Mol. Cell. 2001; 8: Full Text Full Text PDF PubMed Scopus Google Scholar). has been that c-Myc the of cell death by the expression of the and the p53-dependent expression of cell death genes such as Puma J. J. Nature. 2002; PubMed Scopus Google Scholar). were with for and of either serum or oxygen for to cell and the of p53 and p53 target genes were with p53 under oxygen conditions as as serum or oxygen deprivation However, the p53 target genes Puma and Pten were under oxygen conditions or serum deprivation in the of were under either serum or oxygen whereas were not under either These results that p53 is not transcriptionally oxygen deprivation in cells with deregulated c-Myc c-Myc to Cell Death failure of p53 to oxygen deprivation-induced death in cells with deregulated c-Myc expression led us to the of HIF-1 in the of cell death. HIF-1 has been in cell death through the of a member of the Bcl-2 family Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). HIF-1 is a of and Cell Dev. Biol. 1999; PubMed Scopus Google Scholar). The c-Myc was in from and and were with and for the cells were to for by of oxygen deprivation. cells of whereas cells to activate cell were also to for in the of and cell death to similar in the of at These results that transcriptionally HIF is not required for death in cells with deregulated The c-Myc is a of cell proliferation (1Amati B. Brooks M.W. Levy N. Littlewood T.D. Evan G.I. Land H. Cell. 1993; 72: 233-245Abstract Full Text PDF PubMed Scopus (444) Google Scholar). However, cells such as c-Myc are in growth because of or results in an of and growth factors to the tumor expressing c-Myc rapidly undergo death of critical survival the tumor to cells induce the of and to be able to in a survival factors are limiting C.V. Sci. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The of cells for survival is to cell death initiated during loss of survival In this study, we examined cell death initiated during loss of critical survival factors and serum) in rodent fibroblasts expressing conditionally c-Myc. In with the expression of c-Myc itself did not cell death, but in sensitization to either oxygen or serum deprivation. The of c-Myc to sensitize cells to serum or oxygen deprivation a common point in the death machinery cell death signals The release of cytochrome c has been as a point in the death machinery cell death signals (14Juin P. Hueber A.O. Littlewood T. Evan G. Genes Dev. 1999; 13: 1367-1381Crossref PubMed Scopus (303) Google Scholar). In this study, we have demonstrated that cells expressing c-Myc cytochrome c to cell death in response to serum or oxygen deprivation. The overexpression of Bcl-xL death in cells with deregulated expression in response to either oxygen or serum deprivation. Bcl-xL also the release of cytochrome c from the mitochondria and the activation of during oxygen or serum deprivation. The release of cytochrome c is mediated through activation of Bax or Bak (reviewed in Ref. J.C. Green D.R. Nat. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). The loss of Bax and Bak is to resistant to serum or oxygen deprivation-induced cell death D.S. Santore M.T. Lee V.Y. Brunelle J. Budinger G.R. Zong W.X. Thompson C.B. Hay N. Chandel N.S. Mol. Cell. Biol. 2002; 22: 94-104Crossref PubMed Scopus (151) Google Scholar, 29Wei M.C. Zong W.X. Cheng E.H. Lindsten T. Panoutsakopoulou V. Ross A.J. Roth K.A. MacGregor G.R. Thompson C.B. Korsmeyer S.J. Science. 2001; 292: 727-730Crossref PubMed Scopus (3354) Google Scholar). The of Bcl-xL is to the activation of Bax or Bax has been shown as a target of T. Z. Reed J.C. Res. 2000; Google Scholar). Bax the mitochondria of apoptotic cells is in the of c-Myc M.G. J. J. B. Penn L.Z. Mol. Cell. 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Alarcon R. E. P. M. J. Y. Lowe S.W. M. Giaccia A. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar), demonstrated the induction of p53 during oxygen deprivation in is induction of p53 target The failure of p53 to activate genes was to the inability of p53 to with the during oxygen deprivation. the loss of a p53 in is not required for oxygen deprivation-induced cell death, but is required for cell death Science. 2001; PubMed Scopus Google Scholar). Our might also a molecular for a by K. Chen G. Lindsten T. E. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), demonstrated that loss of p53 in cells the is for but not The loss of Bax and Bak in cells is required to in that the lack of oxygen in is able to induce death in cells that have p53 limiting tumor The loss of Bax and Bak be able to oxygen deprivation-induced cell death, cells to a The inability of p53 to regulate cell death during oxygen deprivation led us to whether HIF-1 might be required for cell death. HIF-1 is a regulator of genes during oxygen deprivation Cell Dev. Biol. 1999; PubMed Scopus Google Scholar). Previous studies have both for The of HIF-1 during oxygen deprivation is to the induction of the Bcl-2 family member Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). However, in this study, we cell death to be in that express c-Myc. it which proteins are to regulate oxygen deprivation-induced death in cells with deregulated Our results that oxygen deprivation is to have a cell death that Bcl-2 family to initiate mitochondrial dependent cell death.