Delineation of Two Distinct Type 1 Activation Functions in the Androgen Receptor Amino-terminal Domain

Chamberlain, Nancy L.; Whitacre, David C.; Miesfeld, Roger L.

doi:10.1074/jbc.271.43.26772

Cited by 103 publications

(88 citation statements)

References 33 publications

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“…In addition, androgen treatment does not induce ART-27 mRNA or protein in LNCaP cells and there are no decipherable androgen response elements in the promoter of ART-27. 2 However, ART-27 protein expression may be indirectly regulated by localized secretion of cytokines or growth factors in response to androgen signaling.…”

Section: Discussionmentioning

confidence: 99%

“…They exert biological effects by binding to the androgen receptor (AR), 1 a member of the steroid receptor family of transcription factors. Functional mapping of the androgen receptor shows that several regions are required for transcriptional activation (1,2). These include a C-terminal domain, AF-2, as well as two regions in the N terminus, AF-1a and AF-1b.…”

mentioning

confidence: 99%

“…These include a C-terminal domain, AF-2, as well as two regions in the N terminus, AF-1a and AF-1b. Recent evidence suggests that the AR cell-and promoter-specific transcriptional response is generated through interactions with regulatory proteins termed coactivators and corepressors with AF-1 and AF-2 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

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confidence: 99%

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ART-27, an Androgen Receptor Coactivator Regulated in Prostate Development and Cancer

Taneja

Swenson

et al. 2004

Journal of Biological Chemistry

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Androgen receptor trapped clone-27 (ART-27) is a newly described transcriptional coactivator that binds to the N terminus of the androgen receptor (AR). Given the vital importance of AR signaling in prostate growth and differentiation, we investigated the role of ART-27 in these processes. Immunohistochemical studies indicate that ART-27 protein is expressed in differentiated epithelial cells of adult human prostate and breast tissue. In prostate, ART-27 is abundant in AR-positive prostate luminal epithelial cells, in contrast to the stroma, where cells express AR but not ART-27. The use of a rat model of androgen depletion/reconstitution indicates that ART-27 expression is associated with the elaboration of differentiated prostate epithelial cells. Interestingly, regulated expression of ART-27 in the androgensensitive LNCaP prostate cancer cell line inhibits androgen-mediated cellular proliferation and enhances androgen-mediated transcription of the prostatespecific antigen (PSA) gene. Consistent with a growth suppressive function, we show that ART-27 expression levels are negligible in human prostate cancer. Importantly, examination of ART-27 protein expression in early fetal prostate development demonstrates that ART-27 is detected only when the developing prostate gland has proceeded from a solid mass of undifferentiated cells to a stage in which differentiated luminal epithelial cells are evident. Thus, ART-27 is an AR cofactor shown to be subject to both cell type and developmental regulation in humans. Overall, the results suggest that decreased levels of ART-27 protein in prostate cancer tissue may occur as a result of de-differentiation, and indicate that ART-27 is likely to regulate a subset of AR-responsive genes important to prostate growth suppression and differentiation.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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ART-27, an Androgen Receptor Coactivator Regulated in Prostate Development and Cancer

Taneja

Swenson

et al. 2004

Journal of Biological Chemistry

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“…This is despite the important functional role of the AR NH 2 -terminal domain in transactivation (6). Among the poorly conserved regions are the previously reported AR transactivation subdomains AF1a (rat AR residues 154 -167 and human AR residues 173-186) and AF1b (rat AR residues 295-359 and human AR residues 297-361), which are critical for transcriptional activity (7). Lack of sequence conservation in these regions is surprising and suggests that the NH 2 -terminal FIG.…”

Section: Identification Of An Ar Nh 2 -Terminal Conserved Motif-mentioning

confidence: 99%

“…This region was further resolved into two noncontiguous activation segments, AF1a and AF1b (7). The functional importance of the AR NH 2 -terminal region is supported by the extensive posttranslational modification that occurs in the region, including phosphorylation (8 -10), sumoylation (11), and ubiquitylation (12,13).…”

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confidence: 99%

An Androgen Receptor NH2-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)

He¹,

Bai²,

Hnat³

et al. 2004

Journal of Biological Chemistry

122

113

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The NH 2 -terminal sequence of steroid receptors is highly variable between different receptors and in the same receptor from different species. In this study, a primary sequence homology comparison identified a 14-amino acid NH 2 -terminal motif of the human androgen receptor (AR) that is common to AR from all species reported, including the lower vertebrates. The evolutionarily conserved motif is unique to AR, with the exception of a partial sequence in the glucocorticoid receptor of higher species. The presence of the conserved motif in AR and the glucocorticoid receptor and its absence in other steroid receptors suggests convergent evolution. The function of the AR NH 2 -terminal conserved motif was suggested from a yeast two-hybrid screen that identified the COOH terminus of the Hsp70-interacting protein (CHIP) as a binding partner. We found that CHIP functions as a negative regulator of AR transcriptional activity by promoting AR degradation. In support of this, two mutations in the AR NH 2 -terminal conserved motif previously identified in the transgenic adenocarcinoma of mouse prostate model reduced the interaction between CHIP and AR. Our results suggest that the AR NH 2 -terminal domain contains an evolutionarily conserved motif that functions to limit AR transcriptional activity. Moreover, we demonstrate that the combination of comparative sequence alignment and yeast two-hybrid screening using short conserved peptides as bait provides an effective strategy to probe the structure-function relationships of steroid receptor NH 2 -terminal domains and other intrinsically unstructured transcriptional regulatory proteins.Steroid receptors depend on multiple domains for their function as ligand-dependent transcriptional activators. The DNAand ligand-binding domains have been studied extensively and have a high degree of structural and functional conservation. In contrast, the largely unstructured NH 2 -terminal domains (1-3) are highly variable in size and sequence, and the molecular mechanisms that contribute to transactivation are not well understood. The size of the NH 2 -terminal region of steroid receptors increases with evolutionary expansion (4, 5), from estrogen receptor-␣ (185 amino acid residues) to the glucocorticoid receptor (GR 1 ; 420 residues), androgen receptor (AR; 558 residues), progesterone receptor (B form; 566 residues), and mineralocorticoid receptor (602 residues). In contrast, transcription factors such as p53, NF-B, and VP16 typically have transcriptional activation domains of Ͻ100 residues.

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Androgen insensitivity

Gottlieb

Pinsky

Beitel³

et al. 1999

Am. J. Med. Genet.

116

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The androgen receptor (AR) protein regulates transcription of certain genes. Usually, this activity depends upon a central DNA-binding domain that permits the binding of androgen-AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal androgen-binding domain (ABD) and an N-terminal modulatory domain. These domains interact among themselves and with coregulatory, nonreceptor proteins to determine vector control over a gene's transcription rate. The precise roles of these proteins are active research areas. Severe X-linked androgen receptor gene (AR) mutations cause complete androgen insensitivity, mild ones impair virilization with or without infertility, and moderate ones sometimes yield a wide phenotypic spectrum among sibs. Different expressivity may reflect variability of AR-interactive proteins. The family history must identify heterozygous XX females with sparse, delayed, or asymmetric pubic/axillary hair or delayed menarche and infertile XY maternal aunts or uncles. Mutation type and density vary along the length of the AR. N-terminal polyglutamine tract expansion limits AR transactivation, causing a form of mild androgen insensitivity. Analysis of ABD mutations that do not impair androgen binding or impair it selectively will illuminate its intradomain properties. For partial androgen insensitivity and mild androgen insensitivity, pharmacotherapy with certain androgens or other steroids may overcome some dysfunction of certain mutant ARs. Experience with this approach is limited; outcomes have been generally disappointing.

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Delineation of Two Distinct Type 1 Activation Functions in the Androgen Receptor Amino-terminal Domain

Cited by 103 publications

References 33 publications

ART-27, an Androgen Receptor Coactivator Regulated in Prostate Development and Cancer

ART-27, an Androgen Receptor Coactivator Regulated in Prostate Development and Cancer

An Androgen Receptor NH2-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)

Androgen insensitivity

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