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. 1999 Mar 15;338(Pt 3):799–806.

Dual role for transcription factor AP-2 in the regulation of the major fetal promoter P3 of the gene for human insulin-like growth factor II.

L E Rietveld 1, A M Koonen-Reemst 1, J S Sussenbach 1, P E Holthuizen 1
PMCID: PMC1220119  PMID: 10051455

Abstract

The human insulin-like growth factor II (IGF-II) gene contains four promoters that are differentially active during cell growth and development. Promoter 3 (P3) is the most active promoter in fetal and non-hepatic adult tissues. In addition to its expression during development, P3 is also the major promoter in many tumour tissues and IGF-II-expressing cell lines. Here we show that AP-2 has a dual function in P3 regulation in vivo as well as in vitro. In cells expressing low levels of endogenous AP-2, AP-2 overexpression activates P3, whereas P3 promoter activity is inhibited in cells containing abundant AP-2. Four potential AP-2-binding sites were identified in footprinting studies with recombinant AP-2. One of these AP-2-binding sites is located within the previously identified element P3-4 that contains two adjacent binding sites for IGF-II promoter-binding proteins IPBP3 and IPBP4/5. By applying binding competition assays and mutational analysis it is shown that AP-2 interferes with IPBP3 binding and transactivation in vivo as well as in vitro. Furthermore, AP-2 can bind additional elements in the proximal P3 promoter that also contribute to AP-2-mediated transactivation as shown by transient transfection assays. From these results we conclude that AP-2 is an important regulator in vivo and in vitro of IGF-II P3 activity.

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Selected References

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