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‐s...

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Bibliographic Details
Published in:Developmental dynamics 2009-03, Vol.238 (3), p.664-672
Main Authors: McMullin, Ryan P., Mutton, Laura N., Bieberich, Charles J.
Format: Article
Language:English
Subjects:
Animals
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
colon
Gene Expression Regulation, Developmental - genetics
Genes, Reporter - genetics
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Hoxb13
Male
Mice
Mice, Transgenic
prostate
Prostate - embryology
Prostate - metabolism
Prostatic Neoplasms - embryology
Prostatic Neoplasms - pathology
Regulatory Elements, Transcriptional
TRAMP
Transgenes - genetics
transgenic mouse
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Summary: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. Developmental Dynamics 238:664–672, 2009. © 2009 Wiley‐Liss, Inc.
ISSN:1058-8388
1097-0177
DOI:10.1002/dvdy.21870