Peroxisome proliferator (PP) activated receptors (PPARs) are activated by a wide range of dietary fatty acids, pharmaceuticals, inflammatory mediators, and industrial chemicals. PPs enhance keratinocyte (KC) growth and differentiation and activate KC endogenous PPAR. To some extent, we also know that other proteins, the PPAR coactivators, can greatly influence the transcriptional effect of PPARs via protein-protein interaction. Not all of the coactivators are known, and their tissue and temporal distribution in human epidermis has not been previously studied. We have isolated a presumptive coactivator from human keratinocytes, tentatively named 07a. The overall goal of this proposal is to understand coactivator regulation of PPAR in the context of human KCs using 07a as a paradigm. We will test the hypothesis that the different protein sequences in 07a and an apparent related larger isoform. NRBF-2, contribute to their overall effectiveness as coactivators.
The specific aims of this proposal will focus on the functional differences of 07a and NRBF-2 in gene activation assays and direct interaction with PPAR and other nuclear receptors. Protein-protein interaction will be studied using site directed mutagenesis of 07a, NRBF-2 and the receptors. PPAR activity will be measured with reporters both in the presence and absence of PPAR ligands. Transfection of cultured keratinocyte lines will be used to evaluate the effect of 07a and NRBF-2 on keratinocyte growth and differentiation. Separately and in combination PPs, PPARs and likely PPAR coactivators have great health benefit potential in those clinical areas where promoting KC maturation would be advantageous such as in wound healing and in differentiation therapy of epidermal malignancies establishing the research need to better understand their interaction.
| Flores, Anthony M; Gurevich, Igor; Zhang, Carmen et al. (2011) TNIP1 is a corepressor of agonist-bound PPARs. Arch Biochem Biophys 516:58-66 |
| Gurevich, Igor; Flores, Anthony M; Aneskievich, Brian J (2007) Corepressors of agonist-bound nuclear receptors. Toxicol Appl Pharmacol 223:288-98 |
