The androgen receptor (AR) gene contains a polymorphic trinucleotide repeat region, (CAG)(n), in its N-terminal transactivation domain (NTD) that encodes a polyglutamine (polyQ) tract in the receptor protein. Whereas the length of the CAG repeat ranges from 6 to 39 in healthy individuals, the variations in repeat length both within and outside the normal range are associated with disease, including impaired spermatogenesis and Kennedy's disease, and with the risk of developing breast and prostate cancer. Whereas it has been proposed that the inverse relationship between polyQ tract length within the normal range and AR transactivation potential may be responsible for altered risk of disease, the molecular mechanisms underlying polyQ length modulation of AR function have not been elucidated. In this study, we provide detailed characterization of a somatic AR gene mutation detected in a human prostate tumor that results in interruption of the polyQ tract by two non-consecutive leucine residues (AR-polyQ2L). Compared with wtAR, AR-polyQ2L exhibits disrupted inter-domain communication (N/C interaction) and a lower protein level, but paradoxically has markedly increased transactivation activity. Molecular modeling and the response to cofactors indicate that the increased activity of AR-polyQ2L results from the presentation of a more stable platform for the recruitment of accessory proteins than wild-type AR. Analysis of the relationship between polyQ tract length and AR function revealed a critical size (Q16-Q29) for maintenance of N/C interaction. That between 91 and 99% of AR alleles in different racial-ethnic groups encode a polyQ tract in the range of Q16-Q29 suggests that N/C interaction has been preserved as an essential component of androgen-induced AR signaling.

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These findings suggest that AR is an important determinant of disease relapse in early stage prostate cancer, and that altered AR levels in the malignant epithelial cells or in the peritumoral stroma is indicative of non-organ confined prostate cancer.

SummaryOpsonization of apoptotic cardiocytes by maternal anti-Ro/SSA and anti-La/ SSB antibodies contributes to tissue injury in the neonatal lupus syndrome. The objective of the current study was to quantify the surface membrane expression of Ro/La components during different phases of apoptosis and map the Ro/La apotopes (epitopes expressed on apoptotic cells) bound by cognate antibodies. Multi-parameter flow cytometry was used to define early and late apoptotic populations and their respective binding by monospecific anti-Ro and anti-La IgGs. Anti-Ro60 bound specifically to early apoptotic Jurkat cells and remained accessible on the cell surface throughout early and late apoptosis. In contrast, anti-La bound exclusively to late apoptotic cells in experiments controlled for non-specific membrane leakage of IgG. Ro52 was not accessible for antibody binding on either apoptotic population. The immunodominant NH2-terminal and RNA recognition motif (RRM) epitopes of La were expressed as apotopes on late apoptotic cells, confirming recent in vivo findings. An immunodominant internal epitope of Ro60 that contains the RRM, and is recognized by a majority of sera from mothers of children with congenital heart block (CHB) and patients with primary Sjögren's syndrome, was also accessible as an apotope on early apoptotic cells. The distinct temporal expression of the immunodominant Ro60 and La apotopes indicates that these intracellular autoantigens translocate independently to the cell surface, and supports a model in which maternal antibody populations against both Ro60 and La apotopes act in an additive fashion to increase the risk of tissue damage in CHB.