HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors.
Solid tumors contain regions of hypoxia, a physiological stress that can activate cell death pathways and, thus, result in the selection of cells resistant to death signals and anticancer therapy. Bcl2/adenovirus EIB 19kD-interacting protein 3 (BNIP3) is a cell death factor that is a member of the Bcl-2 proapoptotic family recently shown to induce necrosis rather than apoptosis. Using cDNA arrays and serial analysis of gene expression, we found that hypoxia induces up-regulation of BNIP3 and its homologue, Nip3-like protein X. Analysis of human carcinoma cell lines showed that they are hypoxically regulated in many tumor types, as well as in endothelial cells and macrophages. Regulation was hypoxia inducible factor-1-dependent, and hypoxia inducible factor-1 expression was suppressed by von Hippel-Lindau protein in normoxic cells. Northern blotting and in situ hybridization analysis has revealed that these factors are highly expressed in human tumors compared with normal tissue and that BNIP3 is up-regulated in perinecrotic regions of the tumor. This study shows that genes regulating cell death can be hypoxically induced and are overexpressed in clinical tumors.
Sowter
H M
HM
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom.
Ratcliffe
P J
PJ
Watson
P
P
Greenberg
A H
AH
Harris
A L
AL
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
C090121:BNIP3 protein, human; C116838:BNIP3L protein, human; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins