RESUMEN
We report the second family with AIMP1 deficiency, due to a homozygous truncating AIMP1 (g.107248613 C > T) mutation. This female showed early-onset developmental arrest, intractable epileptic spasms, microcephaly, and a rapid clinical course leading to premature death, associated with cerebral atrophy and myelin deficiency on brain MRI. Clinical and neuroimaging findings are consistent with a primary neuronal degenerative disorder, rather than with the previously reported Perlizaeus-Merzbacher-like phenotype. Given its critical role in neurofilament assembly 16, impaired myelin formation is due to neuronal/axonal dysfunction. We propose that AIMP1 deficiency be added to the differential diagnosis of infantile onset, progressive neurodegenerative disease.
Asunto(s)
Citocinas/deficiencia , Citocinas/genética , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/genética , Proteínas de Unión al ARN/genética , Factores de Edad , Encéfalo/patología , Femenino , Humanos , Recién Nacido , Mutación , Sustancia Blanca/patologíaRESUMEN
A protein factor that can inhibit binding of the androgen-receptor complex to the nuclear chromatin has been isolated from the cytosol of the ventral prostate of rats. The inhibition is reversible and not caused by an irreversible destruction of the receptor or the chromatin. The inhibitor also can promote, by a temperature-dependent process, the release of steroid-receptor complex already bound to chromatin. It is conceivable that such a protein factor plays a regulatory role in the nuclear-cytoplasmic recycling or chromatin binding of the steroid hormone receptor.
Asunto(s)
Cromatina/metabolismo , Próstata/metabolismo , Proteínas/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Esteroides/metabolismo , Núcleo Celular/metabolismo , Citosol/metabolismo , Dihidrotestosterona/metabolismo , Masculino , Membrana Nuclear/metabolismo , TemperaturaRESUMEN
In situ hybridization analysis demonstrated that abundant testicular orphan receptor (TR4) transcripts were detected in kidney, intestine, and bone, which are vitamin D3 target organs. Cell transfection studies also demonstrated that the expression of the vitamin D3 target gene, 25-hydroxyvitamin D3 24-hydroxylase, can be repressed by TR4 through high affinity binding (Kd = 1.32 nM) to the direct repeat 3 vitamin D3 receptor response element (DR3VDRE). This TR4-mediated repression of DR3VDRE is in contrast to our earlier report that TR4 could induce thyroid hormone target genes containing a direct repeat 4 thyroid hormone response element (DR4T3RE). Electrophoretic mobility shift assay using several TR4 monoclonal antibodies when combined with either TR4-DR3VDRE or TR4-DR4T3RE showed a distinct supershifted pattern, and proteolytic analysis further demonstrated distinct digested peptides with either TR4-DR3VDRE or TR4-DR4T3RE. These results may therefore suggest that TR4 can adapt to different conformations once bound to DR3VDRE or DR4T3RE. The consequence of these different conformations of TR4-DR3VDRE and TR4-DR4T3RE may allow each of them to recruit different coregulators. The differential repression of TR4-mediated DR3VDRE and DR4T3RE transactivation by the receptor interacting protein 140, a TR4 coregulator, further strengthens our hypothesis that the specificity of gene regulation by TR4 can be modulated by protein-DNA and protein-protein interactions.
Asunto(s)
Colecalciferol/fisiología , ADN/metabolismo , Regulación Enzimológica de la Expresión Génica , Proteínas del Tejido Nervioso/fisiología , Receptores de Esteroides/fisiología , Receptores de Hormona Tiroidea , Transducción de Señal/fisiología , Hormonas Tiroideas/fisiología , Animales , Células CHO , Cricetinae , Sistema Enzimático del Citocromo P-450/biosíntesis , Sistema Enzimático del Citocromo P-450/genética , Regulación del Desarrollo de la Expresión Génica , Humanos , Hibridación in Situ , Mucosa Intestinal/metabolismo , Riñón/metabolismo , Masculino , Ratones , Unión Proteica , Conformación Proteica , Esteroide Hidroxilasas/biosíntesis , Esteroide Hidroxilasas/genética , Relación Estructura-Actividad , Testículo/metabolismo , Vitamina D3 24-HidroxilasaRESUMEN
The androgen receptor (AR) binds to androgen response elements and regulates target genes via a mechanism involving coregulators. Here we demonstrate that the AR can interact with the testicular orphan receptor-4 (TR4) and function as a repressor to down-regulate the TR4 target genes by preventing the TR4 binding to its target DNA. Interestingly, the heterodimerization of AR and TR4 also allows TR4 to repress AR target gene expression. Simultaneous exposure to both receptors therefore could result in bidirectional suppression of their target genes. Together, these data demonstrate that the coupling of two different receptors, through the heterodimerization of AR and TR4, is a unique signaling pathway in the steroid receptor superfamily, which may facilitate further understanding of the complicated androgen action in prostate cancer or libido.