Nuclear receptors (NRs) are a large family of ligand-regulated transcription factors that play critical roles in tissue specialization and cell differentiation. Ligand activation of tr^e peroxisome proliferator (PP) activated receptor (PPAR) promotes epidermal keratinocyte (KC) maturation and expression of terminal differentiation- specific genes. NRs, including PPARs, do not act alone to regulate transcription but rather have their function modulated by protein-protein interactions with various coregulator proteins. These proteins lead to enzymatic modification of chromatin and/or subsequent transcription complex assembly at the promoters of receptor-regulated genes. Chromatin remodeling or recruitment of additional transcriptional control proteins ultimately leads to decreased or increased gene activity by corepressors or coactivators, respectively. Although studies in other systems indicate importance of both corepressors and coactivators, corepressors are to date less studied and in epidermis little is known about either type of NR coregulator protein. Our overall hypothesis is that coregulator proteins are key to PPAR regulation of PP-responsive and possibly differentiation-specific genes in KCs. Our Preliminary Studies have identified a potentially novel PPAR corepressor derived from screening a keratinocyte cDNA library. To further investigate its governance of PPAR function we will determine i)molecular requirements for association with PPARs, ii) what additional transcription control proteins may be involved, and iii)what effect altered expression of the candidate coregulator has on KC biology. This work will complement previous studies showing PP and PPAR control of keratinocyte differentiation by examining an integral component of transcriptional activity, the coregulator, in this case specifically a corepressor. From their ability to regulate KC differentiation, PPs may have eventual application in dermatotherapies similar to retinoids and vitamin D. This investigation should aid in expanding our basic understanding of PPAR molecular regulation in human KCs and thus contribute to a foundation for eventual clinical PP use in cases such as differentiation therapy of SCC and BCC malignancies.
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