Hoxb13 regulatory elements mediate transgene expression during prostate organogenesis and carcinogenesis.
The prostate requires androgens for development and homeostasis. Prostate cancer shares this dependence, however progression to androgen-independence is common after androgen deprivation. There is considerable interest in achieving therapeutic gene expression after androgen ablation using prostate-specific promoters. Paradoxically, known prostate-restricted cis-regulatory elements are androgen dependent. Hoxb13 expression is restricted in adults to the prostate and colon, and robust Hoxb13 expression persists after castration. To locate regulatory elements conferring this expression pattern, a lacZ reporter was inserted into the Hoxb13 locus on a mouse genomic bacterial artificial chromosome. In transgenic mice, this construct recapitulated the Hoxb13 expression pattern, including expression after castration. Reporter gene activity was maintained during carcinogenesis in a prostate cancer model. Hoxb13 cis-regulatory elements provide a powerful tool to achieve androgen-independent transgene expression in the prostate and distal colon-specific expression in the gastrointestinal tract. These data establish a framework for high-resolution analyses of factors regulating Hoxb13.
McMullin
Ryan P
RP
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland 21250, USA.
Mutton
Laura N
LN
Bieberich
Charles J
CJ
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011467:Prostate / Q000196:embryology* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000196:embryology* / Q000473:pathology*; D050436:Regulatory Elements, Transcriptional; D019076:Transgenes / Q000235:genetics*
D018398:Homeodomain Proteins; C100943:Hoxb13 protein, mouse