ABSTRACT 1,25-(OH)2-vitamin D3 is a pleiotropic secosteroid hormone that regulates cell growth and differentiation in many tissues like skin, intestine, bone and others, in addition to its calcitropic actions. 1,25-(OH)2-vitamin D3 dependent modulation of transcription requires interactions of the nuclear receptors for 1,25-(OH)2- vitamin D3 (VDRnuc) and 9-cis-retinoic acid (RXR). More than 50 genes have been described which respond to l,25-(OH)2-vitamin D3 with modulations in mRNA levels. However, only a small number of 1,25-(OH)2-vitamin D3 response elements has been characterised to date. The ligand-dependent and receptor-mediated signal transduction of 1,25-(OH)2 -vitamin D3 is modulated by nuclear coactivators and corepressors. In addition, rapid effects of 1,25-(OH)2-vitamin D3 occuring within seconds to minutes are mediated by a membrane dependent signaling system (VDRmem). Resulting alterations in ion channel activity, arachidonic acid turnover, PKC activity and others via intracellular signal transcduction cascades modulate gene transcription. Since the VDRnuc plays an important role in bone and other tissues and several mutations are related to bone disorders, l,25-(OH)2-vitamin D3 regulated genes are potentially disease-associated. Early genes are rapidly and transiently responsive to various biological activators. Genes of this group often encode proteins important for signal transduction pathways, cell communication, or cell cycle regulation. Whereas early gene response due to steroid hormones is well established, only recently early responsive genes have been identified which respond to 1,25-(OH)2- vitamin D3 action in human osteoblasts and in human monocytic cells. Modulation of transcription of these genes either results from binding of the VDRnuc to VDRE’s or, alternatively, could be the result of signal transduction related to the VDRmem. Early responsive genes for l,25-(OH)2-vitamin D3 action known until now are associated with inhibition of cell cycle progression, with cell-cell communication and the induction of differentiation programs.
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