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Repression of Vascular Endothelial Growth Factor Expression by the Zinc Finger Transcription Factor ZNF24

¹ Vascular Biology Program, Children's Hospital Boston and ² Department of Surgery and ³ Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts; ⁴ Oncology Research, Centocor R&D, Inc., Malvern, Pennsylvania; and ⁵ Department of Preclinical Oncology and Immunology, Cell Genesys, Inc., San Francisco, California

Requests for reprints: Marsha A. Moses, Department of Surgery, Harvard Medical School, Vascular Biology Program, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115-5737. Phone: 617-919-2207; Fax: 617-730-0231; E-mail: marsha.moses{at}childrens.harvard.edu.

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis. Although many positive regulators of VEGF have been identified, relatively little is known regarding the negative regulation of VEGF expression. We identified a zinc finger transcription factor, ZNF24, that may repress VEGF transcription. An inverse correlation between expression of VEGF and ZNF24 was observed in a series of independent studies. ZNF24 was up-regulated in angiogenic tumor nodules where VEGF expression is significantly decreased compared with preangiogenic nodules. In human breast carcinoma cells cultured under normoxic conditions, ZNF24 levels were significantly up-regulated whereas VEGF levels were low. In contrast, VEGF was significantly increased in hypoxic cells whereas ZNF24 was down-regulated. The same inverse correlation between ZNF24 and VEGF was also observed in 70% of matched cDNA pairs of normal and malignant tissues from human colon and breast biopsies. Overexpression of ZNF24 resulted in a significant down-regulation of VEGF, whereas silencing of ZNF24 with small interfering RNA led to increased VEGF expression. Cotransfection of ZNF24 and a VEGF promoter luciferase reporter construct in MDA-MB-231 cells resulted in a significant decrease in VEGF promoter activity. Taken together, these data suggest that ZNF24 is involved in negative regulation of VEGF and may represent a novel repressor of VEGF transcription. [Cancer Res 2007;67(18):8736–41]