Bcl-2, via Its BH4 Domain, Blocks Apoptotic Signaling Mediated by Mitochondrial Ras

Denis, Gerald V.; Yu, Qiang; Ma, Peihong; Deeds, Linda; Faller, Douglas V.; Chen, Changyan

doi:10.1074/jbc.m210202200

Cited by 47 publications

(45 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…4,5,[29][30][31][32][33] Moreover, some bcl-2 protein interactors, such as the bcl-2 mitochondrial chaperone FKBP38, the orphan nuclear receptor Nur77 and the molecular chaperone HSP90, have been demonstrated to be involved in oxygen-dependent and -independent regulation of the HIF-1a protein. [33][34][35] Even if we recently demonstrated that bcl-2 protein under hypoxic conditions interacts with both HIF-1a and HSP90 proteins contributing to the enhancement of HIF-1a protein stability, 21 we cannot exclude that also other bcl-2 interactors can be involved in bcl-2-induced HIF-1a/VEGF regulation.…”

Section: Discussionmentioning

confidence: 99%

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Trisciuoglio¹,

Gabellini

Desideri³

et al. 2011

Cell Death Differ

View full text Add to dashboard Cite

In addition to act as an antiapoptotic protein, B-cell lymphoma (bcl)-2 can also promote tumor angiogenesis. In this context, we have previously demonstrated that under hypoxia bcl-2 promotes hypoxia-inducible factor-1 (HIF-1)-mediated vascular endothelial growth factor (VEGF) expression in melanoma and breast carcinoma. Here, we report on the role of the BH4 domain in bcl-2 functions, by showing that removal of or mutations at the BH4 domain abrogate the ability of bcl-2 to induce VEGF protein expression and transcriptional activity under hypoxia in human melanoma cells. We have also extended this observation to other human tumor histotypes, such as colon, ovarian and lung carcinomas. The involvement of BH4 on HIF-1a protein expression, stability, ubiquitination and HIF-1 transcriptional activity was also demonstrated in melanoma experimental model. Moreover, we validated the role of the BH4 domain of bcl-2 in the regulation of HIF-1/VEGF axis, demonstrating that BH4 peptide is sufficient to increase HIF-1a protein half-life impairing HIF-1a protein ubiquitination, and to enhance VEGF secretion in melanoma cells exposed to hypoxia. Finally, we found that the mechanism by which bcl-2 regulates HIF-1-mediated VEGF expression does not require BH1 and BH2 domains, and it is independent of antiapoptotic and prosurvival function of bcl-2.

show abstract

Section: Discussionmentioning

confidence: 99%

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Trisciuoglio¹,

Gabellini

Desideri³

et al. 2011

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…35 These domains have been described to be involved in Bcl-2, Bax, and other interacting proteins' hetero-and homodimerizations that consequently modulate apoptosis. 35,36 For instance, the conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis. 37 Our studies indicate that deletion of BH4 domain led to a loss of binding of Bcl-2 with Rap1b, whereas it was unaffected by deletion of other domains, suggesting that the binding is specific ( Figure 5); and conceivably Rap1b stabilizes the antiapoptotic effect of Bcl-2.…”

Section: Discussionmentioning

confidence: 99%

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

Sun

Xie²,

Wada

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

The role of tubular injury in diabetic nephropathy is relatively unknown, despite that apoptosis of tubular epithelial cells is commonly observed in human renal biopsies. The GTPase Ras-proximate-1 (Rap1b) is upregulated in the hyperglycemic state and is known to increase B-Raf, an antiapoptotic effector protein.In this study, the effects of high glucose on renal tubular apoptosis and the potential ability for Rap1b to ameliorate these effects were investigated. In the kidneys of diabetic mice, apoptotic tubular cells and dysmorphic mitochondria were observed, Bcl-2 expression was decreased, and Bax expression was increased. Total Rap1b expression was slightly increased, but its associated GTPase activity was significantly decreased. In vitro, high extracellular glucose led to decreased Bcl-2 expression, reduced Rap1b GTPase activity, and increased levels of both Bax and GTPase activating protein in a proximal tubular cell line (HK-2). These changes were accompanied by increased DNA fragmentation, decreased high molecular weight mitochondrial DNA, altered mitochondrial morphology and function, disrupted Bcl-2-Bax and Bcl-2-Rap1b interactions, and reduced cell survival. Overexpression of Rap1b partially prevents these abnormalities. Furthermore, the BH4 domain of Bcl-2 was found to be required for successful protein-protein interaction between Bcl-2 and Rap1b. In summary, these data suggest that Rap1b ameliorates glucose-induced mitochondrial dysfunction in renal tubular cells.

show abstract

“…The total protein concentrations in the cell lysates were normalised and adjusted to 0.4 M NaCl, 0.5% deoxycholate and 0.05% SDS for immunoblotting (Denis et al, 2003). The samples were separated on a 10% SDS -polyacrylamide gel electrophoresis gel and subsequently transferred to a nitrocellulose membrane.…”

Section: Immunoblotmentioning

confidence: 99%

Phellinus linteus sensitises apoptosis induced by doxorubicin in prostate cancer

et al. 2006

View full text Add to dashboard Cite

It has been demonstrated that the Phellinus linteus (PL) mushroom, which mainly consists of polysaccharides, possesses antitumour activity. The mechanisms of PL against malignant growth remain unknown. The anticancer drug doxorubicin (Dox) has been shown to induce apoptosis via initiating a caspase cascade. In this investigation, we tested the effect of PL on Dox-induced apoptosis in prostate cancer LNCaP cells. We showed that PL or Dox, at relatively low doses, does not induce apoptosis in the cells. However, combination treatment with low doses of PL and Dox results in a synergistic effect on the induction of apoptosis. In this apoptotic process, caspases 8, 3 and BID are cleaved, and the addition of caspase inhibitor z-VADfmk completely blocks apoptosis. In addition, JNK is activated in response to PL or the combination treatment in LNCaP cells. The suppression of JNK partially inhibits the induction of apoptosis elicited by the co-treatment. These findings indicate that PL has a synergistic effect with Dox to activate caspases in prostate cancer LNCaP cells. Our study also suggests that PL has therapeutic potential to augment the magnitude of apoptosis induced by antiprostate cancer drugs.

show abstract

Bcl-2, via Its BH4 Domain, Blocks Apoptotic Signaling Mediated by Mitochondrial Ras

Cited by 47 publications

References 58 publications

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

Phellinus linteus sensitises apoptosis induced by doxorubicin in prostate cancer

Contact Info

Product

Resources

About