There is rapidly evolving evidence for beneficial retinoid actions in preventing or treating clinical tumors. Retinoids are established regulators of gene transcription via activation of retinoid receptors. The key targets of retinoid receptors are unknown. We have discovered a novel pathway of potential major biologic significance that is predicted to regulate retinoid signaling at the level of the receptor and also to provide cross-talk between retinoids and other nuclear receptor family members. Our previous microarray studies discovered that the nuclear receptor co-repressor, receptor interacting protein 140 (RIP140) is a novel direct target of all-trans retinoic acid (RA). RIP140 appears to belong to a novel class of nuclear receptor coregulators since it is able to suppress the function of various agonist-bound hormone receptors. ? ? We propose that the activation of RIP140 may be a general mechanism that regulates RA-mediated G1 arrest in diverse cell contexts through a mechanism of repressional cross-talk among nuclear receptor family members. Based on novel preliminary findings we have designed three specific aims that will establish whether RIP140 plays a critical role in two clinically important areas of retinoid cancer biology. During RA-induced terminal differentiation of human embyronal carcinoma, we will ask whether RA regulation of RIP140 constitutes a programmed negative feedback mechanism which limits the activation of retinoid receptors. In the second system, we will ask whether RIP140 mediates cross-talk between retinoid and estrogen signaling in human breast cancer. The novel hypothesis to be tested is that one mechanism by which retinoids regulate gene expression and biologic phenotype is by transrepression through direct activation of the retinoid target gene RIP140. The three specific aims are designed to probe the mechanistic consequence of RA induction of RIP140 and to establish whether RIP140 plays a central role in regulating retinoid-induced tumor cell differentiation and G1 arrest. We believe RIP140 is an excellent entry point to gain mechanistic insights on the role of coregulator dynamics in hormonal signaling across a broad range of hormones, tumors and tissues. ? ?
