Tissue-specific variation in C4 and Slp gene regulation

Cox, Betty Jo; Robins, Diane M.

doi:10.1093/nar/16.14.6857

Cited by 26 publications

(9 citation statements)

References 31 publications

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“…cell-specific nonreceptor factors in hormonal activation is supported by the fact that C'A9 responds strongly to AR in CV-1 (monkey kidney-derived) cells but not in T-47D human mammary cells (9). This reflects in vivo regulation of Slp, which is expressed in kidney but not in mammary gland (8), despite the presence ofAR in both. Therefore, C'A9 provides a simple model for analysis of androgen-specific gene activation, although additional elements may be required for completely appropriate regulation in vivo.…”

Section: Discussionmentioning

confidence: 96%

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Androgen-specific gene activation via a consensus glucocorticoid response element is determined by interaction with nonreceptor factors.

Adler

Danielsen

Robins

1992

Proc. Natl. Acad. Sci. U.S.A.

125

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A fundamental issue in steroid hormone regulation is the question of how specific transcription is attaine in vivo when several receptors can bind the same DNA sequence in vitro. We report an enhancer of the mouse sex-limited protein (SIp) gene that, unlike previously characterized enhancers, is activated by androgens but not by glucocorticoids or progestins. Potent androgen induction requires both a consensus glucocorticoid (hormone) response element and auxiary elements also present within a 120-base-pair DNA fragment. Cotransfection assays with wild-type and mutant receptors reveal that glucocorticoid receptor can bind, but not transactivate from, the hormone response element within the enhancer. The positive effect of androgen and the null effect of glucocorticoid appear to require the amino-terminal domains of the respective receptors. Thus, exclusive transcriptional response to androgens, and lack of response to glucocorticoids, derives from factor interactions that are determined by the context of the receptor binding site rather than by its distinct sequence.

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Section: Discussionmentioning

confidence: 96%

“…Sip is a duplicated complement C4 gene (5,6) whose expression in several tissues is androgen-dependent due to the influence of an inserted provirus (7,8). A DNA fragment within the 5' proviral long terminal repeat, 2 kilobases (kb) upstream ofSlp, functions as a hormone-dependent enhancer and shows multiple nuclear protein binding .sites (9).…”

mentioning

confidence: 99%

Androgen-specific gene activation via a consensus glucocorticoid response element is determined by interaction with nonreceptor factors.

Adler

Danielsen

Robins

1992

Proc. Natl. Acad. Sci. U.S.A.

125

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“…Rsl variation revealed by differential effects on malespecific target genes. (A) Total liver RNA from congenic and inbred mice was assayed for Slp by RNase protection (RPA), using a probe that also detects Slp's homolog C4 (Cox and Robins 1988). Elevated Slp levels in B10.D2.PL, B10.D2.FM, and 129, relative to B10.D2, females are hallmarks of the rsl phenotype.…”

Section: Variation Of the Rsl Phenotype In Inbred Mouse Strainsmentioning

confidence: 99%

Regulator of sex-limitation (Rsl) encodes a pair of KRAB zinc-finger genes that control sexually dimorphic liver gene expression

Krebs¹,

Larkins²,

Price³

et al. 2003

Genes Dev.

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Sexually dimorphic expression of a broad array of liver proteins involved in reproduction and xenobiotic metabolism is induced at puberty by sex-specific growth hormone patterns. An additional control of sex-dependent gene expression is conferred by Regulator of sex-limitation (Rsl) alleles. In variant rsl mice, females inappropriately express the male Sex-limited protein, Slp. We recently showed that a panel of male-specific liver genes is repressed by Rsl, accentuating sex differences in a hormone-independent manner. Here we map rsl to a region on Chromosome 13 comprised exclusively of KRAB (Kruppel-associated box) zinc-finger protein (ZFP) genes. Among eight Rsl candidate (Rslcan) genes within the critical genetic interval, the recent duplicates Rslcan-4 and Rslcan-9 both harbor mutations in rsl mice (partial deletion and splice-site inactivation, respectively). Transgenesis with bacterial artificial chromosome (BAC) clones encompassing Rslcan-4 restores male-specific MUP (major urinary protein) expression to rsl mice, whereas a BAC containing Rslcan-9 rescues sex-specific expression of Slp and cytochrome P450 Cyp2d9. Thus, the Rslcan-4 and Rslcan-9 paralogs partitioned regulation of their target genes during evolution. This demonstrates the first biological role for a set of KRAB zinc-finger repressor proteins and reveals the molecular basis of a gene-silencing pathway critical for sexual dimorphism.

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“…We have recently described a 120-bp enhancer of the mouse sex-limited protein (Slp) gene that exhibits androgenspecific response in transfection (1), in accord with its expression in several tissues (7). Slp arose from a duplicated fourth component of complement gene that acquired andro-ANDROGEN-SPECIFIC GENE ACTIVATION 6327 gen dependence from a proviral insertion (37).…”

mentioning

confidence: 99%

The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences.

Adler¹,

Scheller²,

Robins³

1993

Mol. Cell. Biol.

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The mechanism by which specific hormonal regulation of gene expression is attained in vivo is a paradox in that several of the steroid receptors recognize the same DNA element in vitro. We have characterized a complex enhancer of the mouse sex-limited protein (Slp) gene that is activated exclusively by androgens but not by glucocorticoids in transfection. Potent androgen induction requires both the consensus hormone response element (HRE) and auxiliary elements residing within the 120-bp DNA fragment C'A9. Multiple nonreceptor factors are involved in androgen specificity, with respect to both the elevation of androgen receptor activity and the inactivity of glucocorticoid receptor (GR), since clustered base changes at any of several sites reduce or abolish androgen induction and do not increase glucocorticoid response. However, moving the HRE as little as 10 bases away from the rest of the enhancer allows GR to function, suggesting that GR is repressed by juxtaposition to particular factors within the androgen-specific complex. Surprisingly, some sequence variations of the HRE itself, within the context of C'A9, alter the stringency of specificity, as well as the magnitude, of hormonal response. These HRE sequence effects on expression correspond in a qualitative manner with receptor binding, i.e., GR shows a threefold difference in affinities for HREs amongst which androgen receptor does not discriminate. Altering the HRE orientation within the enhancer also affects hormonal stringency, increasing glucocorticoid but not androgen response. The effect of these subtle variations suggests that they alter receptor position with respect to other factors. Thus, protein-protein interactions that elicit specific gene regulation are established by the array of DNA elements in a complex enhancer and can be modulated by sequence variations within these elements that may influence selection of precise protein contacts.

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Tissue-specific variation in C4 and Slp gene regulation

Cited by 26 publications

References 31 publications

Androgen-specific gene activation via a consensus glucocorticoid response element is determined by interaction with nonreceptor factors.

Androgen-specific gene activation via a consensus glucocorticoid response element is determined by interaction with nonreceptor factors.

Regulator of sex-limitation (Rsl) encodes a pair of KRAB zinc-finger genes that control sexually dimorphic liver gene expression

The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences.

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