Characterization of cis elements of the probasin promoter necessary for prostate-specific gene expression

Jian Feng Zhang, Nan Gao, David Degraff, Xiuping Yu, Qian Sun, Thomas C. Case, Susan Kasper, Robert J. Matusik

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

BACKGROUND. The androgen-regulated probasin (PB) promoter has been used extensively to target transgenes to the prostate in transgenic mice; however, limited data exist on the mechanism that dictates prostate-specific gene expression. Tissue-specific gene expression involves synergistic effects among transcription factors associated in a complex bound to cis-acting DNA elements. METHODS. Using comprehensive linker scan mutagenesis, enzyme mobility shift and supershift assays, chromatin immunoprecipitation, and transgenic animal studies, we have extensively characterized the prostate-specific PB promoter. RESULTS. We identified a series of nonreceptor transcription factors that are bound to the prostate-specific rat PB promoter. These factors include several ubiquitously distributed proteins known to participate in steroid receptor-mediated transcription. In addition, we identified two tissue-specific DNA elements that are crucial in directing prostate-specific PB expression, and confirmed the functional importance of both elements in transgenic animal studies. These two elements are functionally interchangeable and can be bound by multiple protein complexes, including the forkhead transcription factor FoxA1, a "pioneer factor" that has a restricted distribution to some cells type that are ectoderm and endoderm in origin. Using transgenic mice, we further demonstrate that the minimal PB promoter region (-244/-96 bp) that encompasses these tissue-specific elements results in prostate-specific gene expression in transgenic mice, contains androgen receptor and FoxA1-binding sites, as well as ubiquitous transcription factor binding sites. CONCLUSION. We propose that these sequence-specific DNA-binding proteins, including tissue-restricted and ubiquitous factors, create the first level of transcriptional control, which responds to intracellular pathways that directs prostate-specific gene expression.

Original languageEnglish (US)
Pages (from-to)934-951
Number of pages18
JournalProstate
Volume70
Issue number9
DOIs
StatePublished - Jun 15 2010

Fingerprint

Prostate
Gene Expression
Transgenic Mice
Genetically Modified Animals
Transcription Factors
Binding Sites
Forkhead Transcription Factors
Endoderm
Ectoderm
Steroid Receptors
Chromatin Immunoprecipitation
DNA
DNA-Binding Proteins
Electrophoretic Mobility Shift Assay
probasin
Transgenes
Genetic Promoter Regions
Mutagenesis
Androgens
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Urology

Cite this

Zhang, Jian Feng ; Gao, Nan ; Degraff, David ; Yu, Xiuping ; Sun, Qian ; Case, Thomas C. ; Kasper, Susan ; Matusik, Robert J. / Characterization of cis elements of the probasin promoter necessary for prostate-specific gene expression. In: Prostate. 2010 ; Vol. 70, No. 9. pp. 934-951.
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abstract = "BACKGROUND. The androgen-regulated probasin (PB) promoter has been used extensively to target transgenes to the prostate in transgenic mice; however, limited data exist on the mechanism that dictates prostate-specific gene expression. Tissue-specific gene expression involves synergistic effects among transcription factors associated in a complex bound to cis-acting DNA elements. METHODS. Using comprehensive linker scan mutagenesis, enzyme mobility shift and supershift assays, chromatin immunoprecipitation, and transgenic animal studies, we have extensively characterized the prostate-specific PB promoter. RESULTS. We identified a series of nonreceptor transcription factors that are bound to the prostate-specific rat PB promoter. These factors include several ubiquitously distributed proteins known to participate in steroid receptor-mediated transcription. In addition, we identified two tissue-specific DNA elements that are crucial in directing prostate-specific PB expression, and confirmed the functional importance of both elements in transgenic animal studies. These two elements are functionally interchangeable and can be bound by multiple protein complexes, including the forkhead transcription factor FoxA1, a {"}pioneer factor{"} that has a restricted distribution to some cells type that are ectoderm and endoderm in origin. Using transgenic mice, we further demonstrate that the minimal PB promoter region (-244/-96 bp) that encompasses these tissue-specific elements results in prostate-specific gene expression in transgenic mice, contains androgen receptor and FoxA1-binding sites, as well as ubiquitous transcription factor binding sites. CONCLUSION. We propose that these sequence-specific DNA-binding proteins, including tissue-restricted and ubiquitous factors, create the first level of transcriptional control, which responds to intracellular pathways that directs prostate-specific gene expression.",
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Zhang, JF, Gao, N, Degraff, D, Yu, X, Sun, Q, Case, TC, Kasper, S & Matusik, RJ 2010, 'Characterization of cis elements of the probasin promoter necessary for prostate-specific gene expression', Prostate, vol. 70, no. 9, pp. 934-951. https://doi.org/10.1002/pros.21128

Characterization of cis elements of the probasin promoter necessary for prostate-specific gene expression. / Zhang, Jian Feng; Gao, Nan; Degraff, David; Yu, Xiuping; Sun, Qian; Case, Thomas C.; Kasper, Susan; Matusik, Robert J.

In: Prostate, Vol. 70, No. 9, 15.06.2010, p. 934-951.

Research output: Contribution to journalArticle

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T1 - Characterization of cis elements of the probasin promoter necessary for prostate-specific gene expression

AU - Zhang, Jian Feng

AU - Gao, Nan

AU - Degraff, David

AU - Yu, Xiuping

AU - Sun, Qian

AU - Case, Thomas C.

AU - Kasper, Susan

AU - Matusik, Robert J.

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N2 - BACKGROUND. The androgen-regulated probasin (PB) promoter has been used extensively to target transgenes to the prostate in transgenic mice; however, limited data exist on the mechanism that dictates prostate-specific gene expression. Tissue-specific gene expression involves synergistic effects among transcription factors associated in a complex bound to cis-acting DNA elements. METHODS. Using comprehensive linker scan mutagenesis, enzyme mobility shift and supershift assays, chromatin immunoprecipitation, and transgenic animal studies, we have extensively characterized the prostate-specific PB promoter. RESULTS. We identified a series of nonreceptor transcription factors that are bound to the prostate-specific rat PB promoter. These factors include several ubiquitously distributed proteins known to participate in steroid receptor-mediated transcription. In addition, we identified two tissue-specific DNA elements that are crucial in directing prostate-specific PB expression, and confirmed the functional importance of both elements in transgenic animal studies. These two elements are functionally interchangeable and can be bound by multiple protein complexes, including the forkhead transcription factor FoxA1, a "pioneer factor" that has a restricted distribution to some cells type that are ectoderm and endoderm in origin. Using transgenic mice, we further demonstrate that the minimal PB promoter region (-244/-96 bp) that encompasses these tissue-specific elements results in prostate-specific gene expression in transgenic mice, contains androgen receptor and FoxA1-binding sites, as well as ubiquitous transcription factor binding sites. CONCLUSION. We propose that these sequence-specific DNA-binding proteins, including tissue-restricted and ubiquitous factors, create the first level of transcriptional control, which responds to intracellular pathways that directs prostate-specific gene expression.

AB - BACKGROUND. The androgen-regulated probasin (PB) promoter has been used extensively to target transgenes to the prostate in transgenic mice; however, limited data exist on the mechanism that dictates prostate-specific gene expression. Tissue-specific gene expression involves synergistic effects among transcription factors associated in a complex bound to cis-acting DNA elements. METHODS. Using comprehensive linker scan mutagenesis, enzyme mobility shift and supershift assays, chromatin immunoprecipitation, and transgenic animal studies, we have extensively characterized the prostate-specific PB promoter. RESULTS. We identified a series of nonreceptor transcription factors that are bound to the prostate-specific rat PB promoter. These factors include several ubiquitously distributed proteins known to participate in steroid receptor-mediated transcription. In addition, we identified two tissue-specific DNA elements that are crucial in directing prostate-specific PB expression, and confirmed the functional importance of both elements in transgenic animal studies. These two elements are functionally interchangeable and can be bound by multiple protein complexes, including the forkhead transcription factor FoxA1, a "pioneer factor" that has a restricted distribution to some cells type that are ectoderm and endoderm in origin. Using transgenic mice, we further demonstrate that the minimal PB promoter region (-244/-96 bp) that encompasses these tissue-specific elements results in prostate-specific gene expression in transgenic mice, contains androgen receptor and FoxA1-binding sites, as well as ubiquitous transcription factor binding sites. CONCLUSION. We propose that these sequence-specific DNA-binding proteins, including tissue-restricted and ubiquitous factors, create the first level of transcriptional control, which responds to intracellular pathways that directs prostate-specific gene expression.

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