Molecular mechanisms of dominant negative activity by nuclear hormone receptors.

摘要: Human hereditary syndromes have been divided into three major classes according to Mendelian inheritance patterns-autosomal dominant, autosomal recessive, and X-linked recessive. However, recent advances in molecular biology shed deeper insight the nature of some these as specific gene mutations functional consequences described. Often, are transmitted via germ line. development certain tumors, somatic mutation or a coupled with an inherited defective allele (i.e. tumor suppressor genes such retinoblastoma ~53) is required. Such genetic can be categorized respect their function-gain function (resulting either increased normal acquisition novel function), loss function, dominant negative activity. The latter term refers ability product mutant interfere directly wild type protein (1). Examples each types exist within nuclear hormone receptor superfamily, class ligand-regulatable transcription factors that includes steroid hormone, vitamin D, retinoic acid, thyroid receptors (TRs). These all contain central DNA-binding domain two zinc finger motifs carboxyterminal ligand binding (LBD) which important for well homoand/or heterodimerization other proteins. Several examples gain occurred due chromosomal rearrangements encoding acid (RAR) isoforms, resulting fusion In acute promyelocytic leukemia, PML-RAR proteins formed between myeloid unknown PML, RARcY disrupt subnuclear organization nucleus, perhaps by redirecting retinoid X