Molecular mechanisms of dominant negative activity by nuclear hormone receptors.

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