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Identification of Androgen Response Elements in the Insulin-Like Growth Factor I Upstream Promoter

Department of Veterans Affairs (Y.W., W.Z., J.Z., J.P., Q.W., Y.Z., W.A.B., C.P.C.), Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters Medical Center, Bronx, New York 10468; and Department of Medicine (W.A.B., C.P.C.), Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Christopher Cardozo, Center of Excellence for the Medical Consequences of Spinal Cord Injury, Room 1E-02, James J. Peters Veterans Affairs Medical Center, Bronx, New York 10468. E-mail: Chris.Cardozo{at}mssm.edu.

Testosterone stimulates the expression of IGF-I in cells and tissues that include prostate, muscle and muscle satellite cells, and the uterus. Here, the molecular mechanisms of this effect of testosterone were explored. Testosterone increased IGF-I mRNA levels in HepG2 and LNCaP cells and stimulated the activity of reporter genes controlled by 1.6 kb of the upstream promoter of the human IGF-I gene. An androgen-responsive region that was located between –1320 and –1420 bases upstream of the first codon was identified by truncation studies. The androgen-responsive region was found to contain two sequences resembling known androgen receptor (AR)-binding sites from the Pem1 gene. Reporter genes incorporating these sequences were strongly stimulated by androgens. Each of the androgen-responsive elements (AREs) bound recombinant AR-DNA-binding domain in gel-shift experiments; binding was greatly enhanced by sequences flanking the apparent AR-binding half-sites. Testosterone induced recruitment of AR to sequences of genomic DNA containing these AREs. The two AREs were activated 5-fold more by AR than glucocorticoid receptor. Collectively, these findings indicate the presence of two AREs within the IGF-I upstream promoter that act in cis to activate IGF-I expression. These AREs seem likely to contribute to the up-regulation of the IGF-I gene in prostate tissues, HepG2 cells, and potentially other tissues.

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