Identification of the hypoxia-inducible factor 1 alpha-responsive HGTD-P gene as a mediator in the mitochondrial apoptotic pathway.
Hypoxia-inducible factor 1 alpha (HIF-1 alpha) controls the cellular responses to hypoxia, activating transcription of a range of genes involved in adaptive processes such as increasing glycolysis and promoting angiogenesis. However, paradoxically, HIF-1 alpha also participates in hypoxic cell death. Several gene products, such as BNip3, RTP801, and Noxa, were identified as HIF-1 alpha-responsive proapoptotic proteins, but the complicated hypoxic cell death pathways could not be completely explained by the few known genes. Moreover, molecules linking the proapoptotic signals of HIF-1 alpha directly to mitochondrial permeability transition are missing. In this work, we report the identification of an HIF-1 alpha-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1 alpha through a hypoxia-responsive element on the HGTD-P promoter region. When overexpressed, HGTD-P was localized to mitochondria and facilitated apoptotic cell death via typical mitochondrial apoptotic cascades, including permeability transition, cytochrome c release, and caspase 9 activation. In the process of permeability transition induction, the death-inducing domain of HGTD-P physically interacted with the voltage-dependent anion channel. In addition, suppression of HGTD-P expression by small interfering RNA or antisense oligonucleotides protected against hypoxic cell death. Taken together, our data indicate that HGTD-P is a new HIF-1 alpha-responsive proapoptotic molecule that activates mitochondrial apoptotic cascades.
Lee
Mi-Jung
MJ
Department of Pathology and Medical Research Center for Reactive Oxygen Species, College of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Kim
Jee-Youn
JY
Suk
Kyoungho
K
Park
Jae-Hoon
JH
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009693:Nucleic Acid Hybridization / Q000379:methods; D018272:Porins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D050994:Voltage-Dependent Anion Channels
C486647:FAM162A protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018272:Porins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D050994:Voltage-Dependent Anion Channels; D020169:Caspases