RESUMEN
Genetics plays a role, to a greater or lesser extent, in all diseases. Variations in our DNA and differences in how that DNA functions (alone or in combinations), alongside the environment (which encompasses lifestyle), contribute to disease processes. This review explores the genetic basis of human disease, including single gene disorders, chromosomal imbalances, epigenetics, cancer and complex disorders, and considers how our understanding and technological advances can be applied to provision of appropriate diagnosis, management and therapy for patients.
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Animales , Aberraciones Cromosómicas , ADN/genética , Modelos Animales de Enfermedad , Epigénesis Genética , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/terapia , Variación Genética , Genoma Humano , Humanos , Mosaicismo , Mutación , Neoplasias/genética , Reacción en Cadena de la PolimerasaRESUMEN
We have identified a novel c-Jun N-terminal kinase (JNK)-interacting protein, Sab, by yeast two-hybrid screening. Sab binds to and serves as a substrate for JNK in vitro, and was previously found to interact with the Src homology 3 (SH3) domain of Bruton's tyrosine kinase (Btk). Inspection of the sequence of Sab reveals the presence of two putative mitogen-activated protein kinase interaction motifs (KIMs) similar to that found in the JNK docking domain of the c-Jun transcription factor, and four potential serine-proline JNK phosphorylation sites in the C-terminal half of the molecule. Using deletion and site-directed mutagenesis, we demonstrate that the most N-terminal KIM in Sab is essential for JNK binding, and that, as with c-Jun, physical interaction with JNK is necessary for Sab phosphorylation. Interestingly, confocal immunocytochemistry and cell fractionation studies indicate that Sab is associated with mitochondria, where it co-localizes with a fraction of active JNK. These and previously reported properties of Sab suggest a possible role in targeting JNK to this subcellular compartment and/or mediating cross-talk between the Btk and JNK signal transduction pathways.