Abstract
The antiproliferative activities of the USF proteins and the frequent loss of USF function in cancer cells suggest a role for these ubiquitous transcription factors in tumor suppression. However, the cellular targets that mediate the effects of USF on cellular proliferation and transformation remain uncharacterized. IGF2R, with multiple functions in both normal growth and cancer, was investigated here as a possible USF target in both nontumorigenic and tumorigenic breast cell lines. The 5'-flanking sequences of the human IGF2R gene contain multiple, highly conserved E boxes almost identical to the consensus USF DNA-binding sequence. These E boxes were found to be essential for IGF2R promoter activity in the nontumorigenic mammary epithelial cell line MCF-10A. USF1 and USF2 bound the IGF2R promoter in vitro, and both USF1 and USF2, but not c-Myc, were present within the IGF2R promoter-associated chromatin in vivo. Overexpressed USF2, but not USF1, transactivated the IGF2R promoter, and IGF2R mRNA was markedly decreased by expression of a USF-specific dominant negative mutant, identifying IGF2R as a USF2 target. IGF2R promoter-driven expression was USF-independent in both MCF-7 and MDA-MB-231 breast cancer cell lines, suggesting that a defect in USF function may contribute to down-regulation of IGF2R expression in cancer cells.
Highlights
Whereas c-Myc promotes cellular proliferation and transformation, overexpressed USF has been shown to suppress these processes [5]
We have investigated expression driven by the proximal human insulin-like growth factor 2 receptor (IGF2R) promoter in normal and tumorigenic breast epithelial cells
Expression of a dominant negative mutant specific to USF family members, A-USF, suppressed IGF2R promoter activity in MCF-10A cells (Fig. 5) and markedly decreased IGF2R message levels (Fig. 7), demonstrating that this promoter was activated by endogenous USF and that the cellular IGF2R gene in MCF-10A cells was under USF control
Summary
Vol 278, No 39, Issue of September 26, pp. 37231–37240, 2003 Printed in U.S.A. The IGF2 Receptor Is a USF2-specific Target in Nontumorigenic Mammary Epithelial Cells but Not in Breast Cancer Cells*. The 5-flanking sequences of the human IGF2R gene contain multiple, highly conserved E boxes almost identical to the consensus USF DNA-binding sequence These E boxes were found to be essential for IGF2R promoter activity in the nontumorigenic mammary epithelial cell line MCF-10A. We report a key role for USF in expression of the mannose 6-phosphate/insulin-like growth factor 2 receptor (IGF2R) gene in normal mammary epithelial cells. The role of USF at this promoter was investigated in a cell line with robust endogenous USF activity, the nontumorigenic human breast epithelial cell line MCF-10A These experiments demonstrate that the human IGF2R gene is a target of USF2, but not of c-Myc. the IGF2R promoter is unresponsive to USF in two breast cancer cell lines, providing further evidence for disrupted USF transcriptional activity in cancer cells
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