RESUMO
Steroid receptor RNA activator (SRA), the only known RNA coactivator, augments transactivation by nuclear receptors (NRs). We identified SLIRP (SRA stem-loop interacting RNA binding protein) binding to a functional substructure of SRA, STR7. SLIRP is expressed in normal and tumor tissues, contains an RNA recognition motif (RRM), represses NR transactivation in a SRA- and RRM-dependent manner, augments the effect of Tamoxifen, and modulates association of SRC-1 with SRA. SHARP, a RRM-containing corepressor, also binds STR7, augmenting repression with SLIRP. SLIRP colocalizes with SKIP (Chr14q24.3), another NR coregulator, and reduces SKIP-potentiated NR signaling. SLIRP is recruited to endogenous promoters (pS2 and metallothionein), the latter in a SRA-dependent manner, while NCoR promoter recruitment is dependent on SLIRP. The majority of the endogenous SLIRP resides in the mitochondria. Our data demonstrate that SLIRP modulates NR transactivation, suggest it may regulate mitochondrial function, and provide mechanistic insight into interactions between SRA, SLIRP, SRC-1, and NCoR.
Assuntos
Proteínas Nucleares/metabolismo , RNA não Traduzido/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Neoplasias da Mama/metabolismo , Células COS , Chlorocebus aethiops , Clonagem Molecular , Proteínas de Ligação a DNA , Feminino , Células HeLa , Histona Acetiltransferases , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Mitocôndrias/metabolismo , Dados de Sequência Molecular , Proteínas Nucleares/genética , Correpressor 1 de Receptor Nuclear , Coativador 1 de Receptor Nuclear , Regiões Promotoras Genéticas , Conformação Proteica , RNA Longo não Codificante , RNA não Traduzido/genética , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Alinhamento de Sequência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Tumorais CultivadasRESUMO
Preservation of tissues in glutaraldehyde-based fixatives allows identification of prostatic glandular secretions without resorting to immunostaining. This has enabled detailed histological assessment of the entire male urethra and bladder and has confirmed prostatic epithelial cells outside the confines of the prostate gland. Male and female lower urinary tracts are also compared. Three intact bladders and penile urethras from radical surgical specimens, tissue from 10 radical prostatectomies, 12 penile urethral biopsy specimens, and 40 samples of of metaplastic bladder mucosa were evaluated after undergoing glutaraldehyde-based fixation (Solufix, Tissugen, Western Australia). All sections were immunostained for prostate-specific antigen (PSA) and high molecular-weight cytokeratin. Selected formalin-fixed samples also were assessed and stained for androgen receptor status, and 10 female control subjects also were evaluated. Prostatic epithelial cells, as recognized by their content of prostate secretory granules (PSG), were identified in almost all periurethral glands seen along the length of the penile urethra. These "minor prostatic glands" were composed entirely of prostatic cells or, more commonly, mixed prostatic and mucinous epithelium. The penile urethra was lined by transitional epithelium, whereas the prostatic urethra was lined by glandular cells with superficial androgen receptor-positive cells that had lost much of their secretory function. Foci of cystitis cystica/glandularis contained prostatic cells in more than half of the cases evaluated, and in all cases PSG secretion in extraprostatic sites was commensurate with PSA secretion. No prostatic secretion was seen in the female control cases, and the female urethra, in contrast to the male urethra, was lined entirely by glycogenated stratified squamous epithelium similar to the epithelium lining the vagina and vulva. This study defines the entity of minor prostatic glands and confirms their extensive normal distribution in the adult male subject. Minimal but persistently elevated levels of serum PSA occuring after successful radical prostatectomy may be related in part to this phenomenon. The female lower urinary tract differs considerably from the male but has similar features related to the lower genital tract.
