Secretoglobin 2A1 is under selective androgen control mediated by a peculiar binding site for Sp family transcription factors.
Human secretoglobin (SCGB) 2A1 (or lipophilin C, lacryglobin, mammaglobin B) is a small protein of unknown function that forms heterodimers with secretoglobin 1D1 (lipophilin A) in tears and is expressed in the prostate. Here we show that SCGB 2A1 is under androgen control in the androgen-responsive prostatic cell line LNCaP and can be induced more than 20-fold by dihydrotestosterone. Only 6 h after androgen treatment, a strong DNase I-hypersensitive site is induced in the proximal promoter within chromatin. Within the boundaries of this DNase I-hypersensitive site a minimal 32-bp peculiar dimeric inverted repeat variant GC box (dim-IR-GA box) was found to confer androgen but not glucocorticoid responsiveness in gene transfer experiments. Mutations of both GA boxes that abolish binding of Sp1 and Sp3 also abrogate the androgen response. In an EMSA the DNA binding domain of the androgen receptor (AR) was not able to bind directly to the dim-IR-GA box. However, AR is functionally required for the hormone response because induction can be inhibited with the nonsteroidal antagonist bicalutamide. Chromatin immunoprecipitation experiments demonstrated that AR is recruited to the proximal promoter 10 min after androgen treatment. Therefore we propose that SCGB 2A1 represents a new class of androgen target genes that are purely under indirect AR control mediated by DNA-bound Sp factors.
Xiao
Fei
F
Institut für Anatomie und Zellbiologie, Justus-Liebig-Universität Giessen, Aulweg 123, D-35385 Giessen, Germany.
Mirwald
Andreas
A
Papaioannou
Maria
M
Baniahmad
Aria
A
Klug
Jörg
J
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D060788:Mammaglobin B; D008969:Molecular Sequence Data; D009154:Mutation; D009185:Myelin Proteins; D051839:NFI Transcription Factors / Q000378:metabolism; D009570:Nitriles; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011510:Proteolipids; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D020218:Response Elements / Q000235:genetics*; D060765:Secretoglobins; D051703:Sp Transcription Factors / Q000378:metabolism*; D014105:Tosyl Compounds; D014598:Uteroglobin
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D002352:Carrier Proteins; D002843:Chromatin; D060788:Mammaglobin B; D009185:Myelin Proteins; D051839:NFI Transcription Factors; D009570:Nitriles; D011510:Proteolipids; C556463:SCGB1D1 protein, human; C556467:SCGB2A1 protein, human; D060765:Secretoglobins; D051703:Sp Transcription Factors; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D014598:Uteroglobin; C053541:bicalutamide