Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia

Abstract

The ability to sense and respond to changes in oxygen availability is critical for many developmental, physiological, and pathological processes, including angiogenesis, control of blood pressure, and cerebral and myocardial ischemia. Hypoxia-inducible factor-1␣ (HIF-1␣) is a basic-helix-loop-helix (bHLH)-containing member of the PER-ARNT-SIM (PAS) family of transcription factors that plays a central role in the response to hypoxia. HIF-1␣, and its relatives HIF-2␣͞endothelial PAS domain protein (EPAS) and HIF-3␣, are induced in response to hypoxia and serve to coordinately activate the expression of target genes whose products facilitate cell survival under conditions of oxygen deprivation. When cells are exposed to chronic hypoxia, the protective response can fail, resulting in apoptosis. This study shows that transcription of the gene encoding Nip3, a proapoptotic member of the Bcl-2 family of cell death factors, is strongly induced in response to hypoxia. The Nip3 promoter contains a functional HIF-1-responsive element (HRE) and is potently activated by both hypoxia and forced expression of HIF-1␣. Exposure of cultured cells to chronic hypoxia results in the accumulation of a protein recognized by antibodies raised against Nip3. This study demonstrates a direct link between HIF-1␣ and a proapoptotic member of the Bcl-2 family and offers a reasonable physiological function for members of the Bcl-2 subfamily, including Nip3 and its close relative Nix. These observations indicate that Nip3 may play a dedicated role in the pathological progression of hypoxia-mediated apoptosis, as observed after ischemic injury.

Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors

“…In agreement with the previous reports (Bruick, 2000;Guo et al, 2001), hypoxia induced the expression of Bnip3 in all of the cell lines used in this study. Bnip3 is a mitochondrial protein and induces apoptosis independently of Apaf-1, cytochrome c release and caspase activation .…”

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

“…Of the remaining five lines, two (TALL1 and Raji) expressed only negligible levels of BNIP3, and three (SupT1, PEER and KHM1B) expressed none at all. The earlier findings that under hypoxic conditions expression of BNIP3 can be induced by the transcription factor HIF-1a (Bruick, 2000;Guo et al, 2001;Sowter et al, 2001) prompted us to evaluate the extent to which expression of BNIP3 in haematopoietic tumour cell lines could be induced by hypoxia. Using real-time PCR with cDNA prepared from Jurkat and SupT1 cells incubated under hypoxic conditions, we found that hypoxia leads to increased expression of BNIP3 in Jurkat cells but not in SupT1 cells ( Figure 1B).…”

“…Hypoxia induces expression of a group of genes, among which is the transcriptional regulator HIF-1. BNIP3 is a principle target of HIF-1, and the region containing BNIP3's transcription start site also contains HIF-1-binding sequences (Bruick, 2000;Sowter et al, 2001). It is noteworthy that because HIF-1 is involved in both survival and apoptosis of tumour cells, abrogation of the apoptotic pathway caused by silencing BNIP3 may enhance HIF-1-induced survival signals within tumours.…”

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

“…41 Treated cells were collected with trypsinization, washed twice with PBS, and stained with 150 nM TMRE in PBS in the dark at 371C for 30 min. Samples were washed and resuspended with PBS containing 15 nM TMRE and then analyzed with the FACScan using CellQuest software.…”