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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: John O'Neill who wrote (18851)	4/8/1998 6:43:00 AM
From: Henry Niman	Respond to of 32384

John, Targretin activates RXRs which form heterodimers with many other receptors. Moreover, many of the associated proteins influence RXR activated receptors as well as other activated IRs. Thus, Targretin can synergize with Tamoxifen and many (most?) other SERMs which interact with the estrogen receptor, an IR. IR modulators constitute a significant portion of therapeutic drugs. Here's a recent report on some of the associated proteins that can interact with ERs influenced by Tamoxifen and RARs influenced by retinoids: Proc Natl Acad Sci U S A 1998 Mar 17;95(6):2920-2925 Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Lavinsky RM, Jepsen K, Heinzel T, Torchia J, Mullen TM, Schiff R, Del-Rio AL, Ricote M, Ngo S, Gemsch J, Hilsenbeck SG, Osborne CK, Glass CK, Rosenfeld MG, Rose DW Howard Hughes Medical Institute, Department and School of Medicine, University of California at San Diego, La Jolla, CA 92093-0648, USA. [Medline record in process] Several lines of evidence indicate that the nuclear receptor corepressor (N-CoR) complex imposes ligand dependence on transcriptional activation by the retinoic acid receptor and mediates the inhibitory effects of estrogen receptor antagonists, such as tamoxifen, suppressing a constitutive N-terminal, Creb-binding protein/coactivator complex-dependent activation domain. Functional interactions between specific receptors and N-CoR or SMRT corepressor complexes are regulated, positively or negatively, by diverse signal transduction pathways. Decreased levels of N-CoR correlate with the acquisition of tamoxifen resistance in a mouse model system for human breast cancer. Our data suggest that N-CoR- and SMRT-containing complexes act as rate-limiting components in the actions of specific nuclear receptors, and that their actions are regulated by multiple signal transduction pathways. PMID: 9501191, UI: 98169472