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

To: Flagrante Delictu who wrote (15308)	2/19/1998 9:24:00 AM
From: Henry Niman	Respond to of 32384

Bernie, I was running around getting more articles on the sex gene, but the convergence of two important transcription factors is one of the reasons why I predict that LGND will be extremely successful, the Biotech industry is at the beginning of a very long bull run, LGND will not be taken over by a larger pharmaceutical, and the street has no clue (notice how LGND did NOT put out a press release on this very major discovery?).

To: Flagrante Delictu who wrote (15308)	2/19/1998 9:24:00 AM
From: Henry Niman	Respond to of 32384

Here's what AP had to say about the sex gene: By Malcolm Ritter The Associated Press N E W Y O R K, Feb. 18 - Two genes lock in a tug-of-war to determine whether a mammal embryo will become a boy or a girl, a new study suggests. One of the genes, called Sry, has long been known as the master switch that makes an embryo become male. The new work suggests that a second gene, Dax1, tries to block its effect. It almost always fails. So embryos with one Y chromosome, which carries the Sry gene, and one X chromosome, which carries Dax1, normally develop as males. But in rare cases, the new study suggests, such embryos get an extra copy of the Dax1 gene. And when two Dax1 genes gang up on the single Sry gene, the competition goes the other way, and the embryo becomes a female. Dr. Michael Weiss, who studies the genetics of sex determination at the University of Chicago, called the study an important step toward understanding how genes work together to produce either a male or a female. Other Bodily Implications Understanding the sex-determining pathways, Weiss said, could also shed light on how genes organize themselves to form organs and the immune system. That could lead to new insights into heart disease and rebuilding the battered immune systems of people with AIDS, for example, he said. The study, done in mice, is reported in Thursday's issue of the journal Nature by Amanda Swain and Robin Lovell-Badge of the Medical Research Council National Institute for Medical Research in London, with colleagues there and elsewhere. Scientists already believed that the human version of Dax1 was responsible for overcoming Sry in rare cases in which a woman has both genes, plus an extra bit of a second X chromosome. That extra bit contains several genes, including Dax1. The Dax1 and Sry genes themselves don't compete. Rather, the contest is between the proteins each gene orders the cell to make. Does Dax Have Feminist Agenda? It's not clear whether Dax1 actively encourages female development or just tries to block male development, but the researchers said it appears to be more of a blocker. But if Dax1 almost always fails, why does it even try? Maybe it's a safety mechanism in case Sry fails to work completely, Ms. Swain said. So rather than getting a mix of male and female characteristics, the embryo goes all the way to being female, she suggested. The study developed strains of mice that had extra copies of Dax1. In mice with a normal Sry gene, that just delayed testicle development. But in mice with a weak version of Sry, the Dax1 genes prevailed and the mice became female.

To: Flagrante Delictu who wrote (15308)	2/19/1998 10:22:00 AM
From: Henry Niman	Respond to of 32384

Histone Deacetylase was also implicated in retinoblastomas a couple of weeks ago in Nature: Retinoblastoma protein recruits histone deacetylase to repress transcription The retinoblastoma protein (Rb) silences specific genes that are active in the S phase of the cell cycle and which are regulated by E2F transcription factors. Rb binds to the activation domain of E2F and then actively represses the promoter by a mechanism that is poorly understood. Here we show that Rb associates with a histone deacetylase, HDAC1, through the Rb 'pocket' domain. Association with the deacetylase is reduced by naturally occurring mutations in the pocket and by binding of the human papilloma virus oncoprotein E7. We find that Rb can recruit histone deacetylase to E2F and that Rb cooperates with HDAC1 to repress the E2F-regulated promoter of the gene encoding the cell-cycle protein cyclin E. Inhibition of histone deacetylase activity by trichostatin A (TSA) inhibits Rb-mediated repression of a chromosomally integrated E2F-regulated promoter. Our results indicate that histone deacetylases are important for regulating the cell cycle and that active transcriptional repression by Rb may involve the modification of chromatin structure. A Brehm, E A Miska, D J McCance, J L Reid, A J Bannister & T Kouzarides Retinoblastoma protein recruits histone deacetylase to repress transcription (Letter to Nature) Nature 391, 597 (1998)

To: Flagrante Delictu who wrote (15308)	2/19/1998 10:25:00 AM
From: Henry Niman	Respond to of 32384

Here's another HDAC1 paper on Rb: Retinoblastoma protein represses transcription by recruiting a histonedeacetylase The retinoblastoma tumour-suppressor protein Rb inhibits cell proliferation by repressing a subset of genes that are controlled by the E2F family of transcription factors and which are involved in progression from the G1 to the S phase of the cell cycle. Rb, which is recruited to target promoters by E2F1 (ref. ), represses transcription by masking the E2F1 transactivation domain and by inhibiting surrounding enhancer elements, an active repression that could be crucial for the proper control of progression through the cell cycle. Some transcriptional regulators act by acetylating or deacetylating the tails protruding from the core histones, thereby modulating the local structure of chromatin: for example, some transcriptional repressors function through the recruitment of histone deacetylases. We show here that the histone deacetylase HDAC1 physically interacts and cooperates with Rb. In HDAC1, the sequence involved is an LXCXE motif, similar to that used by viral transforming proteins to contact Rb. Our results strongly suggest that the Rb/HDAC1 complex is a key element in the control of cell proliferation and differentiation and that it is a likely target for transforming viruses. L Magnaghi-Jaulin, R Groisman, I Naguibneva, P Robin, S Lorain, J P Le Villain, F Troalen, D Trouche & A Harel-Bellan Retinoblastoma protein represses transcription by recruiting a histone deacetylase (Letter to Nature) Nature 391, 601 (1998)

To: Flagrante Delictu who wrote (15308)	2/19/1998 10:29:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's Nature's News & Views version of HDAC1 and Rb: TRANSCRIPTIONAL REPRESSION Mutations in the retinoblastoma (Rb) tumour-suppressor protein are implicated in many types of cancer. In healthy cells, Rb binds to the E2F protein, preventing the transcription of genes that would otherwise be activated by E2F. But in cancer cells, this repression is turned off, allowing the cells to enter the cell cycle. In an attempt to find out how Rb normally effects this repression, two groups have found that it binds to the histone deacetylase HDAC1, acting as a bridge to tether this protein to E2F. The HDAC1 protein therefore represses the E2F- regulated promoter, in an interaction that is mediated by Rb. Ronald A. DePinho The cancer-chromatin connection Nature 391, 533-536 (1998)

To: Flagrante Delictu who wrote (15308)	2/19/1998 10:36:00 AM
From: Henry Niman	Read Replies (2) \| Respond to of 32384

Here's more HDAC1 on APL: Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia The transforming proteins of acute promyelocytic leukaemias (APL) are fusions of the promyelocytic leukaemia (PML) and the promyelocytic leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-alpha (RAR-alpha). These proteins retain the RAR-alpha DNA- and retinoic acid (RA)-binding domains, and their ability to block haematopoietic differentiation depends on the RAR-alpha DNA-binding domain. Thus RA-target genes are downstream effectors. However, treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML-RAR-alpha APLs, whereas PLZF-RAR-alpha APLs are resistant to RA. Transcriptional regulation by RARs involves modifications of chromatin by histone deacetylases, which are recruited to RA-target genes by nuclear co-repressors. Here the authors show that both PML- RAR-alpha and PLZF-RAR-alpha fusion proteins recruit the nuclear co-repressor (N-CoR) - histone deacetylase complex through the RAR-alpha CoR box. PLZF-RAR-alpha contains a second, RA-resistant binding site in the PLZF amino-terminal region. High doses of RA release histone deacetylase activity from PML-RAR-alpha, but not from PLZF- RAR-alpha. Mutation of the N-CoR binding site abolishes the ability of PML-RAR-alpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biological effects of PLZF-RAR-alpha from being an inhibitor to an activator of the RA signalling pathway. Therefore, recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of RA on the stability of the PML-RAR-alpha and PLZF-RAR- alpha co-repressor complexes determines the differential response of APLs to RA. F Grignani, S De Matteis, C Nervi, L Tomassoni, V Gelmetti, M Cioce, M Fanelli, M Ruthardt, F F Ferrara, I Zamir, C Seiser, F Grignani, M A Lazar, S Minucci & P G Pelicci Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia (Letter to Nature) Nature 391, 815 (1998)

To: Flagrante Delictu who wrote (15308)	2/19/1998 10:59:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's a Ron Evans' paper showing the same components in non-Hodgkins lymphomas: Proc Natl Acad Sci U S A 1997 Sep 30;94(20):10762-10767 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 U124 Institut National de la Sante et de la Recherche Medicale, Institut de Recherches sur le Cancer de Lille Place de Verdun, F-59045 Lille Cedex France. dhordain@infobiogen.fr 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 (15308)	2/19/1998 11:14:00 AM
From: Henry Niman	Respond to of 32384

Here's the Ron Evan's paper identifying SMART: Nature 1995 Oct 5;377(6548):454-457 A transcriptional co-repressor that interacts with nuclear hormone receptors. Chen JD, Evans RM Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037, USA. Transcriptional silencing mediated by nuclear receptors is important in development, differentiation and oncogenesis. The mechanism underlying this effect is unknown but is one key to understanding the molecular basis of hormone action. Here we identify a receptor-interacting factor, SMRT, as a silencing mediator (co-repressor) for retinoid and thyroid-hormone receptors. SMRT is a previously undiscovered protein whose association with receptors both in solution and bound to DNA-response elements is destabilized by ligand. The interaction with mutant receptors correlates with their transcriptional silencing activities. In vivo, SMRT functions as a potent co-repressor, and a GAL4 DNA-binding domain fusion of SMRT behaves as a frank repressor of a GAL4-dependent reporter. Together, our results identify a new class of cofactors which may be important mediators of hormone action. Comments: Comment in: Nature 1995 Oct 5;377(6548):387-8