Hypoxia induces the expression of the pro-apoptotic gene BNIP3

Guo, Ke; Searfoss, George H.; Krolikowski, David; Pagnoni, M; Franks, Carol F.; Clark, Ken L.; Yu, Ke; Jaye, Michael; Ivashchenko, Yuri

doi:10.1038/sj.cdd.4400810

Cited by 283 publications

(232 citation statements)

References 44 publications

Supporting

Mentioning

215

Contrasting

Order By: Relevance

“…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 .…”

Section: Discussionsupporting

confidence: 94%

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

et al. 2005

View full text Add to dashboard Cite

Low oxygen tension (hypoxia) is a common feature of solid tumors and stimulates the expressions of a variety of genes including those related to angiogenesis, apoptosis and endoplasmic reticulum (ER) stress response. Here we show a close correlation between metastatic potential and the resistance to hypoxia-and ER stress-induced apoptosis among the cell lines with differing metastatic potential derived from Lewis lung carcinoma. An apoptosis-specific expression profiling and immunoblot analyses revealed that the expression of antiapoptotic Mcl-1 increased as the resistance to apoptosis increased. Downregulation of the Mcl-1 expression in the high-metastatic cells by Mcl-1 small interfering RNA increased the sensitivity to hypoxia-induced apoptosis and decreased the metastatic ability. The hypoxia-induced apoptosis was not associated with p53 accumulation, although at present it is not possible to conclude that apoptosis-induced apoptosis is p53-independent. There was no correlation between the expression levels of ER stress-response proteins GADD153, GRP78 and ORP150 and the resistance to hypoxia or ER stresses. In vitro, small numbers of the high-metastatic cells overtook the low-metastatic cells after exposure to several rounds of hypoxia and reoxygenation. In solid tumors initially established from equal mixtures, the proportion of the high-metastatic cells to low-metastatic cells was significantly higher in hypoxic areas. Moreover, the high-metastatic cells were overtaking the low-metastatic cells in some of the tumors. Thus, tumor hypoxia and ER stress may provide a physiological selective pressure for the expansion of the high-metastatic cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors.

show abstract

Section: Discussionsupporting

confidence: 94%

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

et al. 2005

View full text Add to dashboard Cite

show abstract

“…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).…”

Section: Resultsmentioning

confidence: 99%

“…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. Expression of BNIP3, which is induced by hypoxic stimuli (Guo et al, 2001), has been detected in several human cancer cell lines and cardiac myocytes subjected to hypoxia (Crow, 2002;Kubasiak et al, 2002;Regula et al, 2002). In addition, Sowter et al (2003) recently reported that BNIP3 is highly expressed in the hypoxic regions of high-grade breast cancer.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

View full text Add to dashboard Cite

Hypoxia is a key factor contributing to the progression of human neoplasias and to the development of resistance to chemotherapy. BNIP3 is a proapoptotic member of the Bcl-2 protein family involved in hypoxia-induced cell death. We evaluated the expression and methylation status of BNIP3 gene to better understand the role of epigenetic alteration of its expression in haematopoietic tumours. Methylation of the region around the BNIP3 transcription start site was detected in four acute lymphocytic leukaemia, one multiple myeloma and one Burkitt lymphoma cell lines, and was closely associated with silencing the gene. That expression of BNIP3 was restored by treatment with 5-aza2 0 -deoxycytidine (5-aza-dC), a methyltransferase inhibitor, which confirmed the gene to be epigenetically inactivated by methylation. Notably, re-expression of BNIP3 using 5-aza2-dC also restored hypoxia-mediated cell death in methylated cell lines. Acetylation of histone H3 in the 5 0 region of the gene, which was assessed using chromatin immunoprecipitation assays, correlated directly with gene expression and inversely with DNA methylation. Among primary tumours, methylation of BNIP3 was detected in five of 34 (15%) acute lymphocytic leukaemias, six of 35 (17%) acute myelogenous leukaemias and three of 14 (21%) multiple myelomas. These results suggest that aberrant DNA methylation of the 5 0 CpG island and histone deacetylation play key roles in silencing BNIP3 expression in haematopoietic tumours.

show abstract

“…Hif-1a promotes cell death through an increase in p53 or other proapoptotic proteins such as Bcl-2/E1B 19 kDa interacting protein 3 (BNIP3) or BNIP3L (NIX) (Carmeliet et al, 1998;Bruick, 2000;Guo et al, 2001;Sowter et al, 2001). Under most circumstances however, Hif-1a promotes survival of cancer or endothelial cells under hypoxic condition and also protects against apoptosis induced by serum deprivation or by anticancer agents (Alvarez-Tejado, 2001; Sasabe et al, 2005;Piret et al, 2004;Kim et al, 2004a, b;Zhang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

et al. 2006

View full text Add to dashboard Cite

Hypoxia inducible factor-1 (HIF-1) is the major transcription factor and key regulator of adoptive responses to hypoxia. Although it usually promotes tumor cell survival under hypoxia, it has also been implied to trigger apoptosis. Although the impact of hypoxia has been extensively studied in many adult solid tumors, its role in most childhood tumors, for example, in rhabdomyosarcoma (RMS) or Ewing sarcoma (ES), has not yet been addressed. Here, we report that hypoxia protects A204 RMS and A673 ES cells against anticancer drug-or tumor necrosis factor-related apoptosis-inducing ligandinduced apoptosis and that Hif-1a plays a key role in conferring apoptosis resistance under hypoxia. Although a functional HIF-1 pathway and proapoptotic proteins such as p53 and Bcl-2/E1B 19 kDa interacting protein 3 were activated under hypoxia in both A204 RMS and A673 ES cells, these cells remained refractory to apoptosis. Concomitant analysis of antiapoptotic proteins revealed that hypoxia induced expression of Bcl-2 and inhibitor of apoptosis proteins (IAP)-2 as well as proteins associated with anaerobic metabolism such as the glucose transporter protein GLUT-1 and the glycolytic enzyme Aldolase A. Specific downregulation of Hif-1a by RNA interference significantly enhanced apoptosis under hypoxia by preventing the hypoxia-mediated increase in GLUT-1 expression without altering expression levels of the antiapoptotic proteins Bcl-2 or cIAP-2. Moreover, glucose deprivation-induced apoptosis of A204 RMS and A673 ES cells was inhibited under hypoxic conditions in a Hif-1a-dependent manner. As GLUT-1 was induced via Hif-1a under hypoxia in A204 RMS and A673 ES, these findings suggest that the Hif-1a-mediated increase in glucose uptake plays an important role in conferring apoptosis resistance. Thus, hypoxia-inducible genes may represent novel targets for therapeutic intervention in some pediatric tumors, which warrants further investigation.

show abstract

Hypoxia induces the expression of the pro-apoptotic gene BNIP3

Cited by 283 publications

References 44 publications

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

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

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

Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

Contact Info

Product

Resources

About