MDM2 Regulates Vascular Endothelial Growth Factor mRNA Stabilization in Hypoxia
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| Published in: | Molecular and Cellular Biology Vol. 31; no. 24; pp. 4928 - 4937 |
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Expression of vascular endothelial growth factor (VEGF) increases in cancer cells during hypoxia. Herein, we report that the MDM2 oncoprotein plays a role in hypoxia-mediated VEGF upregulation. In studying the characteristics of MDM2 and VEGF expression in neuroblastoma cells, we found that hypoxia induced significantly higher upregulation of both VEGF mRNA and protein in MDM2-positive cells than in the MDM2-negative cells, even in cells without wild-type (wt) p53. We found that hypoxia induced translocation of MDM2 from the nucleus to the cytoplasm, which was associated with increased VEGF expression. Enforcing overexpression of cytoplasmic MDM2 by transfection of the mutant MDM2/166A enhanced expression of VEGF mRNA and protein production, even without hypoxia. The results of mechanistic studies demonstrated that the C-terminal RING domain of the MDM2 protein bound to the AU-rich sequence within the 3' untranslated region (3'UTR) of VEGF mRNA; this binding increased VEGF mRNA stability and translation. In addition, knockdown of MDM2 by small interfering RNA (siRNA) in MDM2-overexpressing cancer cells resulted in inhibition of VEGF protein production, cancer cell survival, and angiogenesis. Our results suggest that MDM2 plays a p53-independent role in the regulation of VEGF, which may promote tumor growth and metastasis. |
| Author | Muxiang Zhou Hailong Zhang Jing He Sheng Zhou Lubing Gu |
| Author_xml | – sequence: 1 givenname: Sheng surname: Zhou fullname: Zhou, Sheng email: mzhou@emory.edu, Zhou71@126.com organization: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology – sequence: 2 givenname: Lubing surname: Gu fullname: Gu, Lubing organization: Department of Pediatrics, Aflac Cancer Center, and Blood Disorders Service, Emory University School of Medicine – sequence: 3 givenname: Jing surname: He fullname: He, Jing organization: Department of Pediatrics, Aflac Cancer Center, and Blood Disorders Service, Emory University School of Medicine – sequence: 4 givenname: Hailong surname: Zhang fullname: Zhang, Hailong organization: Department of Pediatrics, Aflac Cancer Center, and Blood Disorders Service, Emory University School of Medicine – sequence: 5 givenname: Muxiang surname: Zhou fullname: Zhou, Muxiang email: mzhou@emory.edu, Zhou71@126.com organization: Department of Pediatrics, Aflac Cancer Center, and Blood Disorders Service, Emory University School of Medicine |
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Mendeley... Expression of vascular endothelial growth factor (VEGF) increases in cancer cells during hypoxia. Herein, we report that the MDM2 oncoprotein plays a role in... |
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| SubjectTerms | 3' Untranslated Regions Blotting, Western Cell Hypoxia Cell Line, Tumor Enzyme-Linked Immunosorbent Assay Humans Plasmids Proto-Oncogene Proteins c-mdm2 - genetics Proto-Oncogene Proteins c-mdm2 - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA Processing, Post-Transcriptional RNA Stability - genetics RNA, Messenger - genetics RNA, Messenger - metabolism RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Up-Regulation Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism |
| Title | MDM2 Regulates Vascular Endothelial Growth Factor mRNA Stabilization in Hypoxia |
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