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

To: Flagrante Delictu who wrote (13065)	1/7/1998 3:01:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Bernie, When transcription factors (IRs and STATs) get together, they not only form homo and heterodimers, but other proteins pile onto the complex to allow for more regulation. LGND has been interetest in these associated proteins for some time. One was described in their paper on the leptin promoter, back when the news pushed LGND to its all time high of 19 3/4. LGND is at the forefront of reseach on a large group of proteins that control gene expression, not just the ones that are hormone receptors.

To: Flagrante Delictu who wrote (13065)	1/7/1998 3:11:00 PM
From: Henry Niman	Respond to of 32384

Bernie, Here's an abstract on CBP (note that it interacts with several nuclear receptors). Heyman is a LGND scientist and I think that Rosenfeld is on LGND's SAB: A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG Nuclear receptors regulate gene expression by direct activation of target genes and inhibition of AP-1. Here we report that, unexpectedly, activation by nuclear receptors requires the actions of CREB-binding protein (CBP) and that inhibition of AP-1 activity is the apparent result of competition for limiting amounts of CBP/p300 in cells. Utilizing distinct domains, CBP directly interacts with the ligand-binding domain of multiple nuclear receptors and with the p160 nuclear receptor coactivators, which upon cloning have proven to be variants of the SRC-1 protein. Because CBP represents a common factor, required in addition to distinct coactivators for function of nuclear receptors, CREB, and AP-1, we suggest that CBP/p300 serves as an integrator of multiple signal transduction pathways within the nucleus. PMID: 8616895, UI: 96201529

To: Flagrante Delictu who wrote (13065)	1/7/1998 3:16:00 PM
From: Henry Niman	Respond to of 32384

Here's an abstract on SMART (notice that it interacts with RARs and TRs): Corepressor SMRT binds the BTB/POZ repressing domain of the LAZ3/BCL6 oncoprotein. Dhordain P, Albagli O, Lin RJ, Ansieau S, Quief S, Leutz A, Kerckaert JP, Evans RM, Leprince D The LAZ3/BCL6 (lymphoma-associated zinc finger 3/B cell lymphomas 6) gene frequently is altered in non-Hodgkin lymphomas. It encodes a sequence-specific DNA binding transcriptional repressor that contains a conserved N-terminal domain, termed BTB/POZ (bric-a-brac tramtrack broad complex/pox viruses and zinc fingers). Using a yeast two-hybrid screen, we show here that the LAZ3/BCL6 BTB/POZ domain interacts with the SMRT (silencing mediator of retinoid and thyroid receptor) protein. SMRT originally was identified as a corepressor of unliganded retinoic acid and thyroid receptors and forms a repressive complex with a mammalian homolog of the yeast transcriptional repressor SIN3 and the HDAC-1 histone deacetylase. Protein binding assays demonstrate that the LAZ3/BCL6 BTB/POZ domain directly interacts with SMRT in vitro. Furthermore, DNA-bound LAZ3/BCL6 recruits SMRT in vivo, and both overexpressed proteins completely colocalize in nuclear dots. Finally, overexpression of SMRT enhances the LAZ3/BCL6-mediated repression. These results define SMRT as a corepressor of LAZ3/BCL6 and suggest that LAZ3/BCL6 and nuclear hormone receptors repress transcription through shared mechanisms involving SMRT recruitment and histone deacetylation. PMID: 9380707, UI: 98021441

To: Flagrante Delictu who wrote (13065)	1/7/1998 3:18:00 PM
From: Henry Niman	Respond to of 32384

Here are a few more players that pile onto the complex: Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM We report here the identification of a novel cofactor, ACTR, that directly binds nuclear receptors and stimulates their transcriptional activities in a hormone-dependent fashion. ACTR also recruits two other nuclear factors, CBP and P/CAF, and thus plays a central role in creating a multisubunit coactivator complex. In addition, and unexpectedly, we show that purified ACTR is a potent histone acetyltransferase and appears to define a distinct evolutionary branch to this recently described family. Thus, hormonal activation by nuclear receptors involves the mutual recruitment of at least three classes of histone acetyltransferases that may act cooperatively as an enzymatic unit to reverse the effects of histone deacetylase shown to be part of the nuclear receptor corepressor complex. PMID: 9267036, UI: 97410321

To: Flagrante Delictu who wrote (13065)	1/7/1998 3:20:00 PM
From: Andrew H	Read Replies (2) \| Respond to of 32384

Bernie--just what is the problem in getting an invitation to H and Q? I know you have mentioned Murphy positively. Do you subscribe to his newsletter? I would imagine he is frinedly with the H and Q folks and might be helpful, especially if you are a subscriber or if you call for a subscription promptly. It would be a shame if you don't go. Regarding Hawaii, where are you planning on cruising? I lived there for 20 years so if you are going to visit the outer islands, I can recommend some really special places.

To: Flagrante Delictu who wrote (13065)	1/7/1998 3:23:00 PM
From: Henry Niman	Respond to of 32384

Bernie, Here's a broader (and earlier) description of CBP: Nature 1996 Sep 5;383(6595):99-103 Role of CBP/P300 in nuclear receptor signalling. Chakravarti D, LaMorte VJ, Nelson MC, Nakajima T, Schulman IG, Juguilon H, Montminy M, Evans RM The nuclear receptor superfamily includes receptors for steroids, retinoids, thyroid hormone and vitamin D, as well as many related proteins. An important feature of the action of the lipophilic hormones and vitamins is that the maintenance of homeostatic function requires both intrinsic positive and negative regulation. Here we provide in vitro and in vivo evidence that identifies the CREB-binding protein (CBP) and its homologue P300 (refs 6,7) as cofactors mediating nuclear-receptor-activated gene transcription. The role of CBP/P300 in the transcriptional response to cyclic AMP, phorbol esters, serum, the lipophilic hormones and as the target of the E1A oncoprotein suggests they may serve as integrators of extracellular and intracellular signalling pathways. Comments: Comment in: Nature 1996 Sep 5;383(6595):22-3 PMID: 8779723, UI: 96373425

To: Flagrante Delictu who wrote (13065)	1/7/1998 3:25:00 PM
From: Henry Niman	Respond to of 32384

Here's more on SMRT: Proc Natl Acad Sci U S A 1996 Jul 23;93(15):7567-7571 SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers. Chen JD, Umesono K, Evans RM Transcriptional repression represents an important component in the regulation of cell differentiation and oncogenesis mediated by nuclear hormone receptors. Hormones act to relieve repression, thus allowing receptors to function as transcriptional activators. The transcriptional corepressor SMRT was identified as a silencing mediator for retinoid and thyroid hormone receptors. SMRT is highly related to another corepressor, N-CoR, suggesting the existence of a new family of receptor-interacting proteins. We demonstrate that SMRT is a ubiquitous nuclear protein that interacts with unliganded receptor heterodimers in mammalian cells. Furthermore, expression of the receptor-interacting domain of SMRT acts as an antirepressor, suggesting the potential importance of splicing variants as modulators of thyroid hormone and retinoic acid signaling. PMID: 8755515, UI: 96353857

To: Flagrante Delictu who wrote (13065)	1/7/1998 3:32:00 PM
From: Henry Niman	Respond to of 32384

Here's an abstarct on disecting ER activities: Mol Endocrinol 1994 Jan;8(1):21-30 Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Tzukerman MT, Esty A, Santiso-Mere D, Danielian P, Parker MG, Stein RB, Pike JW, McDonnell DP We have used a series of human estrogen receptor (ER) mutants to evaluate the cell- and promoter-specific transcriptional activities of the TAF1 and TAF2 transactivation regions within the human ER. We show that the manifestation of TAF1 or TAF2 function depends strongly upon promoter context; on certain promoters, both the TAF1 and TAF2 activators are required for wild-type transcriptional activity, whereas on other promoters, the TAF1 and TAF2 activators function independently. Using these constructs, we show that the antagonist activity of the triphenylethylene-derived antiestrogens, e.g. tamoxifen, arises from their intrinsic inability to activate ER TAF2 function. However, on certain promoters, these antiestrogens efficiently activate gene transcription through ER. Consistent with this observation, the TAF2 function of the ER is not required on all promoters. In these TAF2-independent promoter contexts, TAF2 function may be provided by a separate transcription factor bound to the promoter. These data suggest that 1) TAF1 may be the major transcriptional activator of the ER; and 2) TAF2 functions as a transcriptional facilitator. On promoters where TAF2 function is provided independently of the ER, the TAF1 function of the ER can function independently of TAF2 activity, allowing triphenylethylene-derived antiestrogens to demonstrate partial agonist activity. These observations provide a possible molecular explanation for the tissue-specific partial agonist properties of tamoxifen and related triphenylethylene antiestrogens observed in vivo. PMID: 8152428, UI: 94203194

To: Flagrante Delictu who wrote (13065)	1/7/1998 3:35:00 PM
From: Henry Niman	Respond to of 32384

Here's one on phosphorylation of STATs: Blood 1994 Sep 15;84(6):1760-1764 Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. Tian SS, Lamb P, Seidel HM, Stein RB, Rosen J Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation and differentiation of progenitor cells of neutrophils by signaling through its receptor (G-CSFR). Although the G-CSFR belongs to the cytokine receptor superfamily, which lacks an intracellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellular proteins is critical for its biologic activities. We report here that JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in response to G-CSF induction. We also demonstrate that the DNA-binding protein STAT3 (also called the acute-phase response factor [APRF], activated by interleukin-6) is an early target of G-CSF-induced tyrosine phosphorylation. G-CSF induces two DNA-binding complexes; the major complex contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins. Antiphosphotyrosine antibody interferes with the DNA binding activity of activated STAT3, indicating that tyrosine phosphorylation of STAT3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF. PMID: 7521688, UI: 94362223