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

To: squetch who wrote (15999)	2/27/1998 2:16:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Stan, The two classes of transcription factors (leucine zippers and zinc fingers) are involved in controlling many genes. I'm not sure about the entire list of cancers, but recent papers have shown defects in acute promyelocytic leukemia, non-Hodgkins lymphoma, acute myelogenous leukemia, and retinoblastomas. These are some of the favorite targets for researchers, so I suspect that as more look at more types of cancers, the list will grow. The various IRs that Ligand targets (more than 75) are all members of the zinc finger class which includes retinoic acid receptors, retinoic acid X receptors, thyroid hormone receptors, vitamin D receptors, estrogen receptors, androgen receptors, mineralocorticoid receptors, gluccocorticoid receptors, HNF4 receptors, and many of the orphan receptors such as LXR (the above list is by no means complete).

To: squetch who wrote (15999)	2/27/1998 8:20:00 PM
From: Henry Niman	Respond to of 32384

Speaking of broader indications, a report just came out indicating that women with high levels of the retinoblastoma related gene (rb2) had a better chance of surviving endometrial cancer. As noted in the articles I uploaded last week, histone deacytylase was associated with the rb gene product: techstocks.com Many tumor types (bone, bladder, lung, cervix, and breast) also show altered rb gene expression (looks like we are starting to get "news on request"): Friday February 27 7:01 PM EST Gene Tied To Endometrial Cancer Survival NEW YORK (Reuters) -- Women with endometrial cancer are less likely to have a cancer recurrence and more likely to survive if they have relatively high levels of a specific gene in their tumor cells, a new study suggests. A test for the gene, Rb2/p130, may one day help determine if certain cancer patients need more aggressive treatment than others, according to a report in the Journal of Clinical Oncology. A new study of 100 women undergoing surgery for cancer found that those with low levels of Rb2/p130 in their tumor cells were nearly five times as likely as other cancer patients to have a cancer recurrence or to die of the disease in the five years after surgery. None of the patients had any chemotherapy or radiation treatment before the surgery. Cancer of the endometrium or uterine lining is the most common malignancy in the female genital tract, but it responds to treatment if caught early. However, 20% of women with the cancer do eventually die of the disease, half of whom were diagnosed at an early stage, noted senior investigator Dr. Antonio Giordano, an associate professor at Thomas Jefferson University in Philadelphia, Pennsylvania. "The study of molecular biologic characteristics, which can also be evaluated before surgery, could prove to be invaluable in selecting patients who bear an aggressive tumor and may influence the choice of the treatment in each case," wrote Giordano and colleagues from the University of Florence and Second University of Naples in Italy. The Rb2/p130 is a newly discovered gene related to the retinoblastoma gene, which most likely acts as a tumor suppressor. Alterations in the retinoblastoma gene have been seen in cancers of the bone, bladder, lung, cervix, and breast. SOURCE: Journal of Clinical Oncology (1998;16:1085-1093)

To: squetch who wrote (15999)	2/27/1998 8:31:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

The Nature abstracts are now on-line. Here's one on rb and histone deacetylase: Nature 1998 Feb 5;391(6667):601-605 Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain JP, Troalen F, Trouche D, Harel-Bellan A Laboratoire Oncogenese, Differenciation et Transduction du Signal, CNRS UPR 9079, Villejuif, France. [Medline record in process] 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, 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. PMID: 9468140, UI: 98127658

To: squetch who wrote (15999)	2/27/1998 8:32:00 PM
From: Henry Niman	Respond to of 32384

Here's another one: Nature 1998 Feb 5;391(6667):597-601 Retinoblastoma protein recruits histone deacetylase to repress transcription. Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T Wellcome/CRC Institute and Department of Pathology, University of Cambridge, UK. [Medline record in process] 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. PMID: 9468139, UI: 98127657

To: squetch who wrote (15999)	2/27/1998 8:37:00 PM
From: Henry Niman	Respond to of 32384

Here's a paper tying p53 to histone deacetylase. Mutations in p53 are the most common alterations in suppressor genes found in human cancer: Protein acetylation: more than chromatin modification to regulate transcription. Bayle JH, Crabtree GR Departments of Pathology and Developmental Biology Howard Hughes Medical Institute Beckman Center for Molecular and Genetic Medicine Stanford University School of Medicine Palo Alto, CA, 94305, USA. [Medline record in process] Histone acetyltransferases and deacetylases are involved in the regulation of gene transcription. Recently, tumor suppressor protein p53 has been shown to be a target for transcriptional coactivators that have histone acetyltransferase activity, suggesting acetylation is also involved in the regulation of cell proliferation and tumorigenesis. PMID: 9427654, UI: 98089188

To: squetch who wrote (15999)	2/27/1998 8:40:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's an abstract on a review of histones controlling cell division and differentiation through transcription factors: Cell Biol Int 1996 Jan;20(1):41-49 Transcriptional control of cell cycle progression: the histone gene is a paradigm for the G1/S phase and proliferation/differentiation transitions. Stein GS, Stein JL, Van Wijnen AJ, Lian JB Department of Cell Biology, University of Massachusetts Cancer Center, Worcester 01655, USA. The histone gene is a paradigm for transcriptional control at the G1/S phase transition point in the cell cycle. The histone gene promoter provides a blueprint for integration of regulatory signals which mediate responsiveness to factors controlling competency for cell cycle progression at the initiation of DNA replication. The downregulation of proliferation at the onset of differentiation is accompanied by and functionally linked to modifications in protein-DNA and protein-protein interactions at histone gene promoter regulatory elements. Chromatin structure, nucleosome organization and gene-nuclear matrix interactions facilitate crosstalk between regulatory sequences and targeting of transcription factors to cognate binding domains. Publication Types: Review Review, tutorial PMID: 8936406, UI: 9709049

To: squetch who wrote (15999)	2/27/1998 8:44:00 PM
From: Henry Niman	Respond to of 32384

Here's another review. This one is on interactions between the rb protein and transcription factors: Semin Cancer Biol 1995 Apr;6(2):91-98 Transcriptional control by the retinoblastoma protein. Kouzarides T Wellcome/CRC Institute, Cambridge, UK. The retinoblastoma gene product is an abundant nuclear protein whose 'pocket domain' mediates numerous protein-protein interactions. A substantial proportion of the RB-interacting proteins are transcription factors suggesting that RB plays a fundamental role in the regulation of transcription. Via these interactions, RB can influence both the progression through the cell cycle and the expression of lineage specific products. In this review I discuss some of the likely mechanisms by which RB regulates cell proliferation and differentiation. Publication Types: Review Review, tutorial PMID: 7647311, UI: 95375243

To: squetch who wrote (15999)	2/27/1998 8:47:00 PM
From: Henry Niman	Respond to of 32384

Here's a review on histone deacetylases and MAD/MAX: Curr Biol 1997 Aug 1;7(8):R505-R507 Transcriptional control: calling in histone deacetylase. Kiermaier A, Eilers M Zentrum fur Molekulare Biologie, Heidelberg, Germany. Mad proteins are transcriptional repressors that antagonize transcriptional activation and transformation by Myc oncoprotein; recent findings suggest that they repress transcription by recruiting histone deacetylases to target sites on DNA.

To: squetch who wrote (15999)	2/27/1998 8:53:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's a recent paper (last month) involving some of our favorite players (heterduplexes with RXR and TR, thyroid hormone receptor) as well as histone deacetylases and effects of an inhibitor (Trichostatin A): EMBO J 1998 Jan 15;17(2):520-534 Distinct requirements for chromatin assembly in transcriptional repression by thyroid hormone receptor and histone deacetylase. Wong J, Patterton D, Imhof A, Guschin D, Shi YB, Wolffe AP Laboratory of Molecular Embryology, National Institute of Child Health and Human Development, Bethesda, MD 20892-5431, USA. Histone deacetylase and chromatin assembly contribute to the control of transcription of the Xenopus TRbetaA gene promoter by the heterodimer of Xenopus thyroid hormone receptor and 9-cis retinoic acid receptor (TR-RXR). Addition of the histone deacetylase inhibitor Trichostatin A (TSA) relieves repression of transcription due to chromatin assembly following microinjection of templates into Xenopus oocyte nuclei, and eliminates regulation of transcription by TR-RXR. Expression of Xenopus RPD3p, the catalytic subunit of histone deacetylase, represses the TRbetaA promoter, but only after efficient assembly of the template into nucleosomes. In contrast, the unliganded TR-RXR represses templates only partially assembled into nucleosomes; addition of TSA also relieves this transcriptional repression. This result indicates the distinct requirements for chromatin assembly in mediating transcriptional repression by the deacetylase alone, compared with those needed in the presence of unliganded TR-RXR. In addition, whereas hormone-bound TR-RXR targets chromatin disruption as assayed through changes in minichromosome topology and loss of a regular nucleosomal ladder on micrococcal nuclease digestion, addition of TSA relieves transcriptional repression but does not disrupt chromatin. Thus, TR-RXR can facilitate transcriptional repression in the absence of hormone through mechanisms in addition to recruitment of deacetylase, and disrupts chromatin structure through mechanisms in addition to the inhibition or release of deacetylase. PMID: 9430643, UI: 98094373

To: squetch who wrote (15999)	2/27/1998 8:59:00 PM
From: Henry Niman	Respond to of 32384

Speaking of favorite players. Here's LGND consultant Bert O'Malley, histone deacetylase, and the progesterone receptor: Proc Natl Acad Sci U S A 1997 Jul 22;94(15):7879-7884 Steroid receptor induction of gene transcription: a two-step model. Jenster G, Spencer TE, Burcin MM, Tsai SY, Tsai MJ, O'Malley BW Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Coactivators, such as steroid receptor coactivator 1 (SRC-1A) and CREB (cAMP response element binding protein)-binding protein (CBP), are required for efficient steroid receptor transactivation. Using an in vitro transcription assay, we found that progesterone receptor (PR)-driven transcription is inhibited by a dominant negative PR ligand-binding domain-interacting region of SRC-1A, indicating that SRC-1A is required for actual transcriptional processes. In addition, these coactivators also possess intrinsic histone acetyltransferase (HAT) activity and bind to each other and another HAT, p300/CBP-associated factor. Here we show that the human PR also interacts with p300/CBP-associated factor in vitro. Recruitment of multiple HATs to target promoters suggests an important role for chromatin remodeling in transcriptional activation of genes by steroid receptors. In transient transfection assays, we found that addition of a histone deacetylase inhibitor, trichostatin A, strongly potentiated PR-driven transcription. In contrast, directing histone deacetylase-1 (HD1) to a promoter using the GAL4 DNA binding domain inhibited transcription. Furthermore, PR transactivation was repressed by recruiting HD1 into the PR-DNA complex by fusing HD1 to a PR ligand-binding domain-interacting portion of SRC-1. Collectively, these results suggest that targeted histone acetylation by recruited HAT cofactors and histone deacetylation are important factors affecting PR transactivation. Recruitment of coactivators and HATs by the liganded PR in vivo may result in (i) remodeling of transcriptionally repressed chromatin to facilitate assembly and (ii) enhanced stabilization of the preinitiation complex by the activation functions of coactivators and the liganded PR itself. PMID: 9223281, UI: 97368286

To: squetch who wrote (15999)	2/27/1998 9:03:00 PM
From: Henry Niman	Respond to of 32384

Here's one (on MAD/MAX) of the 5 histone deacetylase papers in the May 2, 1997 issue of Cell: Cell 1997 May 2;89(3):349-356 Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Laherty CD, Yang WM, Sun JM, Davie JR, Seto E, Eisenman RN Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA. Transcriptional repression by Mad-Max heterodimers requires interaction of Mad with the corepressors mSin3A/B. Sin3p, the S. cerevisiae homolog of mSin3, functions in the same pathway as Rpd3p, a protein related to two recently identified mammalian histone deacetylases, HDAC1 and HDAC2. Here, we demonstrate that mSin3A and HDAC1/2 are associated in vivo. HDAC2 binding requires a conserved region of mSin3A capable of mediating transcriptional repression. In addition, Mad1 forms a complex with mSin3 and HDAC2 that contains histone deacetylase activity. Trichostatin A, an inhibitor of histone deacetylases, abolishes Mad repression. We propose that Mad-Max functions by recruiting the mSin3-HDAC corepressor complex that deacetylates nucleosomal histones, producing alterations in chromatin structure that block transcription. PMID: 9150134, UI: 97294378

To: squetch who wrote (15999)	2/27/1998 9:06:00 PM
From: Henry Niman	Respond to of 32384

Here's another May 2 paper (on leucine zippers): Cell 1997 May 2;89(3):341-347 Histone deacetylase activity is required for full transcriptional repression by mSin3A. Hassig CA, Fleischer TC, Billin AN, Schreiber SL, Ayer DE Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. Members of the Mad family of bHLH-Zip proteins heterodimerize with Max to repress transcription in a sequence-specific manner. Transcriptional repression by Mad:Max heterodimers is mediated by ternary complex formation with either of the corepressors mSin3A or mSin3B. We report here that mSin3A is an in vivo component of large, heterogeneous multiprotein complexes and is tightly and specifically associated with at least seven polypeptides. Two of the mSin3A-associated proteins, p50 and p55, are highly related to the histone deacetylase HDAC1. The mSin3A immunocomplexes possess histone deacetylase activity that is sensitive to the specific deacetylase inhibitor trapoxin. mSin3A-targeted repression of a reporter gene is reduced by trapoxin treatment, suggesting that histone deacetylation mediates transcriptional repression through Mad-Max-mSin3A multimeric complexes. PMID: 9150133, UI: 97294377

To: squetch who wrote (15999)	2/27/1998 9:07:00 PM
From: Henry Niman	Respond to of 32384

Here's the third May 2 paper: Cell 1997 May 2;89(3):357-364 Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex. Zhang Y, Iratni R, Erdjument-Bromage H, Tempst P, Reinberg D Howard Hughes Medical Institute, Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854, USA. An important event in gene expression is the covalent modification of histone proteins. We have found that the mammalian transcriptional repressor Sin3 (mSin3) exists in a complex with histone deacetylases HDAC1 and HDAC2. Consistent with the observation that mSin3-mediated repression of transcription involves the modification of histone polypeptides, we found that the mSin3-containing complex includes polypeptides that tether the mSin3 complex to core histone proteins. In addition, two novel mSin3-associated polypeptides, SAP18 and SAP30, were identified. We isolated a cDNA encoding human SAP18 and found that SAP18 is a component of an mSin3-containing complex in vivo. Moreover, we demonstrate a direct interaction between SAP18 and mSin3. SAP18 represses transcription in vivo when tethered to the promoter, consistent with the ability of SAP18 to interact with mSin3. PMID: 9150135, UI: 97294379

To: squetch who wrote (15999)	2/27/1998 9:09:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's the 4th paper: Cell 1997 May 2;89(3):365-371 Repression by Ume6 involves recruitment of a complex containing Sin3 corepressor and Rpd3 histone deacetylase to target promoters. Kadosh D, Struhl K Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA. Sin3 and Rpd3 negatively regulate a diverse set of yeast genes. A mouse Sin3-related protein is a transcriptional corepressor, and a human Rpd3 homolog is a histone deacetylase. Here, we show that Sin3 and Rpd3 are specifically required for transcriptional repression by Ume6, a DNA-binding protein that regulates genes involved in meiosis. A short region of Ume6 is sufficient to repress transcription, and this repression domain mediates a two-hybrid and physical interaction with Sin3. Coimmunoprecipitation and two-hybrid experiments indicate that Sin3 and Rpd3 are associated in a complex distinct from TFIID and Pol II holoenzyme. Rpd3 is specifically required for repression by Sin3, and artificial recruitment of Rpd3 results in repression. These results suggest that repression by Ume6 involves recruitment of a Sin3-Rpd3 complex and targeted histone deacetylation. PMID: 9150136, UI: 97294380