DIFFERENTIAL GENE REGULATION IN NORMAL & TRANSFORMED KERATINOCYTES BY 1,25(OH)2

University Of California, San Francisco, San Francisco CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The active metabolites of vitamin D and vitamin A show promise in the prevention and treatment of a number of malignancies including squamous cell carcinoma (SCC). 1,25(OH)2D regulates gene expression through its nuclear hormone receptor VDR. VDR partners with the retinoic X (RXR) and retinoic acid (RAR) receptors which bind the active metabolites of vitamin A, 9cis retinoic acid (9cisRA) and all trans retinoic acid (tRA), respectively. VDR, RXR, and RAR form heterodimers, which stimulate gene expression through specific sequences of DNA in the promoter of genes called hormone response elements. Different vitamin D responsive genes have different response elements and are differentially regulated by 1,25(OH)2D and RA in normal human keratinocytes (NHK). Squamous carcinoma cell lines (SCC) fail to respond to 1,25(OH)2D or RA in the same manner as NHK. The SCC lines we have studied have normal levels of VDR with normal binding of the VDR to its ligand and normal binding of the VDR to the vitamin D response elements (VDRE). Therefore, the explanation for the loss of response of SCC to 1,25(OH)2D has been unclear. However, it has recently been discovered that nuclear hormone receptors such as VDR, RAR, and RXR interact with a number of coactivators and cosuppressors which link the nuclear hormone receptors bound to their respective response elements to the transcription initiation complex where transcription by RNA polymerase II begins. During the previous funding period we discovered that the principal binding complex to VDR in nuclear extracts from undifferentiated normal keratinocytes is DRIP (vitamin D receptor interacting protein), a complex essentially identical to TRAP (thyroid receptor activating protein) and ARC (activator-recruited cofactor) which were identified by their binding to other nuclear hormone receptors. During normal keratinocyte differentiation DRIP is downregulated. Its binding to VDR is replaced by two SRC (steroid receptor coactivator). More recently we found that hairless acts as a suppressor of VDR action. We are currently involved in determining the factors that mediate this suppressor action of hairless on VDR.