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.
Mesh Terms:
Animals, Apoptosis, Caspases, Cells, Cultured, Enzyme Activation, Gene Expression Regulation, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Mitochondria, Mitochondrial Proteins, Nucleic Acid Hybridization, Porins, Promoter Regions, Genetic, Protein Biosynthesis, RNA, Small Interfering, Transcription Factors, Transcription, Genetic, Voltage-Dependent Anion Channels
Animals, Apoptosis, Caspases, Cells, Cultured, Enzyme Activation, Gene Expression Regulation, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Mitochondria, Mitochondrial Proteins, Nucleic Acid Hybridization, Porins, Promoter Regions, Genetic, Protein Biosynthesis, RNA, Small Interfering, Transcription Factors, Transcription, Genetic, Voltage-Dependent Anion Channels
Mol. Cell. Biol.
Date: May. 01, 2004
PubMed ID: 15082785
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