ABCB1 p.Pro402Ala
| Predicted by SNAP2: | A: D (59%), C: D (63%), D: D (71%), E: D (63%), F: D (71%), G: D (71%), H: D (59%), I: D (66%), K: D (66%), L: D (66%), M: D (59%), N: D (63%), Q: D (59%), R: D (71%), S: D (53%), T: D (63%), V: D (63%), W: D (71%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Zinc downregulates HIF-1alpha and inhibits its act... PLoS One. 2010 Dec 13;5(12):e15048. Nardinocchi L, Pantisano V, Puca R, Porru M, Aiello A, Grasselli A, Leonetti C, Safran M, Rechavi G, Givol D, Farsetti A, D'Orazi G
Zinc downregulates HIF-1alpha and inhibits its activity in tumor cells in vitro and in vivo.
PLoS One. 2010 Dec 13;5(12):e15048., [PMID:21179202]
Abstract [show]
BACKGROUND: Hypoxia inducible factor-1alpha (HIF-1alpha) is responsible for the majority of HIF-1-induced gene expression changes under hypoxia and for the "angiogenic switch" during tumor progression. HIF-1alpha is often upregulated in tumors leading to more aggressive tumor growth and chemoresistance, therefore representing an important target for antitumor intervention. We previously reported that zinc downregulated HIF-1alpha levels. Here, we evaluated the molecular mechanisms of zinc-induced HIF-1alpha downregulation and whether zinc affected HIF-1alpha also in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that zinc downregulated HIF-1alpha protein levels in human prostate cancer and glioblastoma cells under hypoxia, whether induced or constitutive. Investigations into the molecular mechanisms showed that zinc induced HIF-1alpha proteasomal degradation that was prevented by treatment with proteasomal inhibitor MG132. HIF-1alpha downregulation induced by zinc was ineffective in human RCC4 VHL-null renal carcinoma cell line; likewise, the HIF-1alphaP402/P564A mutant was resistant to zinc treatment. Similarly to HIF-1alpha, zinc downregulated also hypoxia-induced HIF-2alpha whereas the HIF-1beta subunit remained unchanged. Zinc inhibited HIF-1alpha recruitment onto VEGF promoter and the zinc-induced suppression of HIF-1-dependent activation of VEGF correlated with reduction of glioblastoma and prostate cancer cell invasiveness in vitro. Finally, zinc administration downregulated HIF-1alpha levels in vivo, by bioluminescence imaging, and suppressed intratumoral VEGF expression. CONCLUSIONS/SIGNIFICANCE: These findings, by demonstrating that zinc induces HIF-1alpha proteasomal degradation, indicate that zinc could be useful as an inhibitor of HIF-1alpha in human tumors to repress important pathways involved in tumor progression, such as those induced by VEGF, MDR1, and Bcl2 target genes, and hopefully potentiate the anticancer therapies.
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No. Sentence Comment
184 The plasmid reporter used were the VEGF-luc vector that contains the hypoxia response elements (HREs) of VEGF gene promoter cloned upstream of a luciferase transcriptional reporter and the VEGF-luc reporter mutated in the HRE sites [24] (kindly provided by C. Gaetano, IDI, IRCCS, Rome, Italy), the ODD-luc plasmid that encodes fusion proteins consisting of HIF-1a (aa 530-652, a unique oxygen-dependent degradation domain (ODD) fused to the N terminus of firefly luciferase [25]; the expression vectors encoding the dominant negative form of HIF-1a without DNA binding domain and transactivation domain (pCEP4-HIF-1aDN) [23] (kindly provided by B.H. Jiang, Nanjing Medical University, China), the Flag-tagged HIF-1a expression vector and the Flag-tagged HIF-1a with prolyl mutations P402A and P564A [26] (kindly provided by G.L. Semenza, The Johns Hopkins University School of Medicine, Baltimore, MD, USA) were also used.
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ABCB1 p.Pro402Ala 21179202:184:784
status: NEW