Androgen receptor function is modulated by the tissue‐specific AR45 variant

Abstract

A naturally occurring variant of the human androgen receptor (AR) named AR45 has been identified. It lacks the entire region encoded by exon 1 of the AR gene and is composed of the AR DNA‐binding domain, hinge region and ligand‐binding domain, preceded by a novel seven amino‐acid long N‐terminal extension. A survey of human tissues revealed that AR45 was expressed mainly in heart and skeletal muscle. In cotransfection experiments, AR45 inhibited AR function, an effect necessitating intact DNA‐ and ligand‐binding properties. Overexpression of AR45 reduced the proliferation rate of the androgen‐dependent LNCaP cells, in line with the repressive effects of AR45 on AR growth‐promoting function. AR45 interacted with the AR N‐terminal domain in two‐hybrid assays, suggesting that AR inhibition was due to the formation of AR–AR45 heterodimers. Under conditions where the transcriptional coactivator TIF2 or the oncogene β‐catenin were overexpressed, AR45 stimulated androgen‐dependent promoters in presence of dihydrotestosterone. AR45 activity was triggered additionally by the adrenal androgen androstenedione in presence of exogenous TIF2. Altogether, the data suggest an important role of AR45 in modulating AR function and add a novel level of complexity to the mode of action of androgens.

Evidence of androgen action in endometrial and ovarian cancers

“…In addition, a novel 45 kDa AR isoform (AR45) that was discovered in 2005 was found to be expressed in the uterus and shown to be a negative regulator of AR by interacting with the AR NTD (Ahrens-Fath et al 2004).…”

Phylogenetic conservation of the androgen receptor AR45 variant form in placental mammals

“…In presence of the AR however, AR45 acts as an antagonist, provided the levels are high enough (Ahrens-Fath et al, 2005;Haendler, 2005). AR is expressed to a varying extent in most tissues and cell types.…”

“…The recently described AR45 variant form lacks the region encoded by exon 1, which is replaced by a short, unique amino-acid-long stretch originating from a newly described exon 1B identified in the first intron of the AR gene. Exon 1B is located approximately 22 kb downstream of AR exon 1 and 74 kb upstream of AR exon 2 (Ahrens-Fath et al, 2005). A search in public databases led to the identification of the AR gene in the following placental mammals: Pan troglodytes (chimpanzee), Pongo pygmaeus (orang-utan), Macaca mulatta (Rhesus macaque), Callithrix jacchus (marmoset), Loxondonta africana (African elephant), Canis familiaris (domestic dog), Sus scrofa domestica (domestic pig), Mus musculus (mouse) and Rattus norvegicus (Norway rat).…”

“…Semi-quantitative PCR experiments have shown human AR45 to be mainly expressed in heart (Ahrens-Fath et al, 2005). We quantified AR45 transcript levels in three different M. fascicularis organs and compared them to AR mRNA levels (Table 1).…”

“…AR transcripts lacking the exon 3 region coding for part of the DBD have been identified in patients with androgen insensitivity syndrome (Quigley et al, 1992;Ris-Stalpers et al, 1994) and in human breast cancer samples (Zhu et al, 1997). AR45 is the only AR variant form that has so far been described in normal human tissue and the corresponding transcripts are predominantly detected in the heart (Ahrens-Fath et al, 2005). The deduced protein possesses a short, seven amino-acid-long N-terminal stretch instead of the long N-terminal domain found in the AR.…”