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Exp Lung Res. 2011 Mar;37(2):82-91. doi: 10.3109/01902148.2010.521617. Epub 2010 Dec 4.

Bcl-X(L) is the primary mediator of p21 protection against hyperoxia-induced cell death.

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  • 1Department of Biomedical Genetics, School of Medicine and Dentistry, The University of Rochester, Rochester, New York 14642, USA.

Abstract

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.

PMID:
21128858
[PubMed - indexed for MEDLINE]
PMCID:
PMC3749887
Free PMC Article

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