Molecular Endocrinology, Vol 9, 424-434, Copyright © 1995 by Endocrine Society

ARTICLES

Postnatal liver-specific expression of human insulin-like growth factor- II is highly stimulated by the transcriptional activators liver- enriched activating protein and CCAAT/enhancer binding protein-alpha

RJ Rodenburg, W Teertstra, PE Holthuizen and JS Sussenbach
Laboratory for Physiological Chemistry, Graduate School of Developmental Biology, Utrecht University, The Netherlands.

Transcription of the human gene encoding insulin-like growth factor II (IGF-II) is directed by four promoters (P1-P4), which are active in a tissue- and development-dependent manner. High levels of IGF-II in postnatal serum are due to activation of P1 in the liver. Since liver tissue contains high levels of the bZIP factors, liver-enriched activating protein (LAP), the CCAAT/enhancer binding protein-alpha (C/EBP alpha), and the D-element binding protein (DBP), and since P1 contains a functional C/EBP alpha binding site (P1 CBS), we have examined the role of these transcription factors in the activation of IGF-II P1. Transient transfection experiments reveal that P1 can be activated up to 15-fold by LAP and up to 6-fold by C/EBP alpha but can not be activated by DBP. Electrophoretic mobility shift assays with liver nuclear extract show that P1 CBS is predominantly bound by LAP and C/EBP alpha. Mutational analysis of P1 CBS indicates that DBP binding is prevented by one distinct G-C base pair in the P1 CBS element. The P1 CBS element is a high affinity binding site, which was demonstrated by comparing P1 CBS with other LAP-C/EBP alpha binding sites employing quantitative electrophoretic mobility shift assay. These results indicate that LAP and C/EBP alpha are major contributors to the postnatal liver-specific activation of the human IGF-II promoter P1.

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