Bcl-X(L) is the primary mediator of p21 protection against hyperoxia-induced cell death.
A tight balance between anti- and proapoptotic members of the Bcl-2 family controls cell survival and death. Exposure to hyperoxia shifts this balance towards a prodeath state that ultimately activates Bak- and Bax-dependent cell death. Mechanisms underlying this shift are undefined; however, the cell cycle inhibitor p21 delays the loss of antiapoptotic Mcl-1 and Bcl-X(L), and protects against hyperoxia. Here, H1299 human lung adenocarcinoma cells are used to investigate how these and other members of the Bcl-2 family cooperate with p21 to protect against hyperoxia. Expression of antiapoptotic Mcl-1 and Bcl-X(L), but not Bcl-2 or A1, declined during hyperoxia, whereas proapoptotic Bak, but not Bax, increased. Conditional overexpression of p21 selectively delayed the loss of Mcl-1 and Bcl-X(L), without affecting expression of the other members. siRNA knockdown of Mcl-1 and Bcl-X(L) sensitized cells to hyperoxia, but only the loss of Bcl-X(L) ablated the protective effects of p21. Conversely, overexpression of Mcl-1 and Bcl-X(L) protected against hyperoxia, but only Bcl-X(L) bound Bak and Bax. Altogether, these data suggest that Bcl-X(L) is the primary mediator by which p21 protects against hyperoxia-induced Bak/Bax-dependent cell death.
Department of Biomedical Genetics, School of Medicine and Dentistry, The University of Rochester, Rochester, New York 14642, USA.
Yu-Chieh M
YC
Wu
Michael A
MA
O'Reilly
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010100:Oxygen / Q000008:administration & dosage*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C494772:BAK1 protein, human; C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D010100:Oxygen