Sp1 is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism

被引:194
作者
Pore, N
Liu, S
Shu, HK
Li, B
Haas-Kogan, D
Stokoe, D
Milanini-Mongiat, J
Pages, G
O'Rourke, DM
Bernhard, E
Maity, A [1 ]
机构
[1] Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19004 USA
[2] Univ Penn, Sch Med, Dept Neurosurg, Philadelphia, PA 19004 USA
[3] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Inst Canc Res, San Francisco, CA 94143 USA
[5] Inst Signaling Dev Biol & Canc Res, F-06189 Nice 2, France
关键词
D O I
10.1091/mbc.E04-05-0374
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Increased expression of vascular endothelial growth factor (VEGF) contributes to the growth of many tumors by increasing angiogenesis. Although hypoxia is a potent inducer of VEGF, we previously showed that epidermal growth factor receptor amplification and loss of PTEN, both of which can increase phosphatidylinositol-3-kinase (PI3K) activity, increase VEGF expression. Using both adenoviral vectors and a cell line permanently expressing constitutively active myristoylated Akt (myrAkt), we show that activation of Akt, which is downstream of PI3K, increases VEGF expression in vitro and increases angiogenesis in a Matrigel plug assay. Transient transfection experiments using reporter constructs containing the VEGF promoter showed that up-regulation of VEGF by Akt is mediated through Sp1 binding sites located in the proximal promoter. Small interfering RNA directed against Sp1 prevented the induction of VEGF mRNA in response to myrAkt but not to hypoxia. Expression of myrAkt is associated with increased phosphorylation of Sp1 and its increased binding to a probe corresponding to the -88/-66 promoter region. In conclusion, our results indicate that Sp1 is required for transactivation of the VEGF by Akt. Others have proposed that the PI3K/Akt pathway can increase VEGF expression via the hypoxia-inducible factor 1 (HIF-1); however, our results suggest an alternative mechanism can also operate.
引用
收藏
页码:4841 / 4853
页数:13
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