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DISTINCT ROLES OF THE MOLECULAR CHAPERONE HSP90 IN MODULATING DIOXIN RECEPTOR FUNCTION VIA THE basic helix-loop-helix AND PAS DOMAINS

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MOLECULAR AND CELLULAR BIOLOGY 1995年第2期15卷 756-765页

作者： ANTONSSON, C WHITELAW, ML MCGUIRE, J GUSTAFSSON, JA POELLINGER, L HUDDINGE UNIV HOSP KAROLINSKA INSTDEPT MED NUTRS-14186 HUDDINGESWEDEN HUDDINGE UNIV HOSP KAROLINSKA INSTDEPT BIOSCIS-14186 HUDDINGESWEDEN

The intracellular dioxin receptor mediates signal transduction by dioxin and functions as a ligand-activated transcription factor. It contains a basic helix-loop-helix (bHLH) motif contiguous with a Per-Amt-Sim (PAS) homology region. In extracts from nonstimulated cells the receptor is recovered in an inducible cytoplasmic form associated with the 90-kDa heat shock protein (hsp90), a molecular chaperone, We have reconstituted ligand dependent activation of the receptor to a DNA-binding form by using the dioxin receptor and its bHLH-PAS partner factor Amt expressed by in vitro translation in reticulocyte lysate. Deletion of the PAS domain of the receptor resulted in constitutive dimerization with Amt. In contrast, this receptor mutant showed low levels of xenobiotic response element-binding activity, indicating that the PAS domain may be important for DNA-binding affinity and/or specificity of the receptor. It was not possible to reconstitute dioxin receptor function with proteins expressed in wheat germ lysate. In line with these observations, reticulocyte lysate but not wheat germ lysate promoted the association of de novo synthesized dioxin receptor with hsp90. At least two distinct domains of the receptor mediated interaction with hsp90: the ligand-binding domain located within the PAS region and, surprisingly the bHLH domain. Whereas ligand-binding activity correlated ,vith association with hsp90, bHLH-hsp90 interaction appeared to be important for DNA binding activity but not for dimerization of the receptor. Several distinct roles for hsp90 in modulating dioxin receptor function are therefore likely: correct folding of the ligand-binding domain, interference with Amt heterodimerization, and folding of a DNA-binding conformation of the bHLH domain. Thus, the dioxin receptor system provides a complex and interesting model of the regulation of transcription factors by hsp90.

关键词： .distinct deletion bHLH dimerization DNA-binding reconstituted modulating basic helix-loop-helix dioxin ARNT lysate receptor function Wheat germ reticulocyte PAS Domains

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Development. Editorial overview

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Current opinion in neurobiology 1998年第1期8卷 13-7页

作者： M Tessier-Lavigne S L Zipursky Howard Hughes Medical Institute Departments of Anatomy and of Biochemistry and Biophysics University of California 513 Parnassus Avenue San Francisco California 94143-0452 USA Howard Hughes Medical Institute Department of Biological Chemistry 5748 MacDonald Research Laboratories University of California 10833 LeConte Avenue Los Angeles California 90095 USA

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Conservation of the Drosophila lateral inhibition pathway in human lung cancer: A hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1997年第10期94卷 5355-5360页

作者： Chen, H Thiagalingam, A Chopra, H Borges, MW Feder, JN Nelkin, BD Baylin, SB Ball, DW JOHNS HOPKINS MED INST DEPT SURGBALTIMOREMD 21231 JOHNS HOPKINS MED INST DEPT MEDBALTIMOREMD 21231 JOHNS HOPKINS MED INST CTR ONCOLBALTIMOREMD 21231 MERCATOR GENET MENLO PKCA 94025

The achaete-scute genes encode essential transcription factors in normal Drosophila and vertebrate nervous system development. Human achaete-scute homolog-1 (hASH1) is constitutively expressed in a human lung cancer with neuroendocrine (NE) features, small cell lung cancer (SCLC), and is essential for development of the normal pulmonary NE cells that most resemble this neoplasm. Mechanisms regulating achaete-scute homolog expression outside of Drosophila are presently unclear, either in the context of the developing nervous system or in normal or neoplastic cells with NE features, We now provide evidence that the protein hairy-enhancer-of-split-1 (HES-1) acts in a similar manner as its Drosophila homolog, hairy, to transcriptionally repress achaete-scute expression, HES-1 protein is detected at abundant levels in most non-NE human lung cancer cell lines which lack hASH1 but is virtually absent in hASH1-expressing lung cancer cells. Moreover, induction of HES-1 in a SCLC cell line down-regulates endogenous hASH1 gene expression. The repressive effect of HES-1 is directly mediated by binding of the protein to a class C site in the hASH1 promoter. Thus, a key part of the process that determines neural fate in Drosophila is conserved in human lung cancer cells, Furthermore, modulation of this pathway may underlie the constitutive hASH expression seen in NE tumors such as SCLC, the most virulent human lung cancer.

关键词： neuroendocrine hairy-enhancer-of-split-1 transcriptional regulation small cell lung cancer basic helix-loop-helix

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NeuroD1/beta 2 contributes to cell-specific transcription of the proopiomelanocortin gene

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MOLECULAR AND CELLULAR BIOLOGY 1997年第11期17卷 6673-6682页

作者： Poulin, G Turgeon, B Drouin, J INST RECH CLIN MONTREAL GENET MOL LABMONTREALPQ H2W 1R7CANADA

NeuroD1/beta 2 is a basic helix-loop-helix (bHLH) factor expressed in the endocrine cells of the pancreas and in a subset of neurons as they undergo terminal differentiation. We now show that NeuroD1 is expressed in corticotroph cells of the pituitary gland and that iii is involved in cell-specific transcription of the proopiomelanocortin (POMC) gene, It was previously shown that corticotroph-specific POMC transcription depends in part on the action of cell-restricted bHLH factors that were characterized as the CUTE (corticotroph upstream transcription element) (M. Therrien and J. Drouin, Mel. Cell, Biol. 13:2342-2353, 1993) complexes, We now demonstrate that these complexes contain NeuroD1 in association with various ubiquitous bHLH dimerization partners. The NeuroD1-containing heterodimers specifically recognize and activate transcription from the POMC promoter E box that confers transcriptional specificity, Interestingly, the NeuroD1 heterodimers activate transcription in synergy with Ptx1, a Bicoid-related homeodomain protein, which also contributes to corticotroph specificity of POMC transcription, In the adult pituitary gland, NeuroD1 transcripts are detected in POMC-expressing cortisotroph cells, Taken together with the restricted pattern of Ptx1 expression, these results suggest that these two factors establish the basis of a combinatorial code for the program of corticotroph-specific gene expression.

关键词： .subset pituitary contributes basic helix-loop-helix PTX bHLH factors Proopiomelanocortin Cute corticotroph POMC transcription POMC promoter NeuroD heterodimers

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Signaling through mitogen-activated protein kinase and Rac/Rho does not duplicate the effects of activated ras on skeletal myogenesis

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MOLECULAR AND CELLULAR BIOLOGY 1997年第7期17卷 3547-3555页

作者： Ramocki, MB Johnson, SE White, MA Ashendel, CL Konieczny, SF Taparowsky, EJ PURDUE UNIV DEPT SCI BIOLW LAFAYETTEIN 47907 PURDUE UNIV DEPT MED CHEM & MOL PHARMACOLW LAFAYETTEIN 47907 UNIV TEXAS SW MED CTRDEPT CELL BIOL & NEUROSCIDALLASTX 75235

The ability of basic helix-loop-helix muscle regulatory factors (MRFs), such as MyoD, to convert nonmuscle cells to a myogenic lineage is regulated by numerous growth factor and oncoprotein signaling pathways, Previous studies have shown that H-Ras 12V inhibits differentiation to a skeletal muscle lineage by disrupting MRF function via a mechanism that is independent of the dimerization, DNA binding, and inherent transcriptional activation properties of the proteins, To investigate the intracellular signaling pathway(s) that mediates the inhibition of MRF-induced myogenesis by oncogenic Ras, we tested two transformation-defective H-Ras 12V effector domain variants for their ability to alter terminal differentiation, H-Ras 12V,35S retains the ability to activate the Raf/MEK/mitogen-activated protein (MAP) kinase cascade, whereas H-Ras 12V,40C is unable to interact directly with Raf-1 yet still influences other signaling intermediates, including Rac and Rho, Expression of each H-Ras 12V variant in C3H10T1/2 cells abrogates MyoD-induced activation of the complete myogenic program, suggesting that MAP kinase-dependent and -independent Ras signaling pathways individually block myogenesis in this model system. However, additional studies with constitutively activated Rac1 and RhoA proteins revealed no negative effects on MyoD-induced myogenesis. Similarly, treatment of Ras-inhibited myoblasts with the MEK1 inhibitor PD98059 revealed that elevated MAP kinase activity is not a significant contributor to the H-Ras 12V effect. These data suggest that an additional Ras pathway, distinct from the well-characterized MAP kinase and Rac/Rho pathways known to be important for the transforming function of activated Ras, is primarily responsible for the inhibition of myogenesis by H-Ras 12V.

关键词： .protein kinase MAP kinase signaling pathways activated Ras myogenic MyoD mitogen-activated Ras effector oncogenic Ras basic helix-loop-helix MRFs Skeletal myogenesis Rac/Rho

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Relax promotes ectopic neuronal differentiation in Xenopus embryos

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1997年第16期94卷 8602-8605页

作者： Ravassard, P Vallin, J Mallet, J IcardLiepkalns, C HOP LA PITIE SALPETRIERE CNRSUMR C9923LAB GENET MOL NEUROTRANSMISS & PROCESSUS DEGENERAF-75013 PARISFRANCE INST CURIE CNRS UMR 144LAB MORPHOGENESE CELLULAIRE & PROGRESS TUMORALEF-75248 PARIS 05FRANCE

We previously isolated a novel rat cDNA encoding a basic helix-loop-helix transcription factor named Relax, whose expression in the developing central nervous system is strictly limited to discrete domains containing precursor cells. The timing of Relax expression coincides with neuronal differentiation, To investigate the involvement of Relax in neurogenesis we tested whether Relax activated neural genes in the ectoderm by injecting Relax RNA into Xenopus embryos. We demonstrate that ectopic Relax expression induces a persistent enlargement of the neural plate and converts presumptive epidermal cells into neurons, This indicates that Relax, when overexpressed in Xenopus embryos, has a neuronal fate-determination function, Analyses both of Relax overexpression in the frog and of the distribution of Relax in the rat neural Lube strongly suggest that Relax is a neuronal fate-determination gene.

关键词： basic helix-loop-helix ectopic expression neurogenesis cell fate

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Hairy mediates dominant repression in the Drosophila embryo

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EMBO JOURNAL 1997年第10期16卷 2883-2891页

作者： Barolo, S Levine, M UNIV CALIF BERKELEY DIV GENETDEPT MOL & CELL BIOLBERKELEYCA 94720 UNIV CALIF SAN DIEGO DEPT BIOLCTR MOL GENETLA JOLLACA 92093

hairy encodes a bHLH repressor that regulates several developmental processes in Drosophila, including embryonic segmentation and neurogenesis. Segmentation repressors such as Kruppel and knirps have been shown to function over short distances, less than 50-100 bp, to inhibit or quench closely linked upstream activators. This mode of repression permits multiple enhancers to work independently of one another within a modular promoter, Here, we employ a transgenic embryo assay to present evidence that hairy acts as a dominant repressor, which can function over long distances to block multiple enhancers. hairy is shown to repress a heterologous enhancer, the rhomboid NEE, when bound 1 kb from the nearest upstream activator, Moreover, the binding of hairy to a modified NEE leads to the repression of both the NEE and a distantly linked mesoderm-specific enhancer within a synthetic modular promoter. Additional evidence that hairy is distinct from previously characterized embryonic repressors stems from the analysis of the gypsy insulator DNA. This insulator selectively blocks the hairy repressor, but not the linked activators, within a modified NEE. We compare hairy with previously characterized repressors and discuss the consequences of short-range and long-range repression in development.

关键词： basic helix-loop-helix development Drosophila long-range dominant repressor neuroectodermal enhancer

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Development. The end of the beginning?

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Current opinion in neurobiology 1997年第1期7卷 3-6页

作者： A Lumsden Y N Jan Department of Developmental Neurobiology United Medical and Dental School Guy's Hospital London SE1 9RT UK Howard Hughes Medical Institute University of California at San Francisco California USA

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THE basic helix-loop-helix PROTEIN UPSTREAM STIMULATING FACTOR REGULATES THE CARDIAC VENTRICULAR MYOSIN LIGHT-CHAIN 2-GENE VIA INDEPENDENT CIS REGULATORY ELEMENTS

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MOLECULAR AND CELLULAR BIOLOGY 1994年第11期14卷 7331-7339页

作者： NAVANKASATTUSAS, S SAWADOGO, M VANBILSEN, M DANG, CV CHIEN, KR UNIV CALIF SAN DIEGO CTR MOLEC GENETDEPT MEDLA JOLLACA 92093 UNIV CALIF SAN DIEGO PROGRAM BIOMED SCILA JOLLACA UNIV CALIF SAN DIEGO AMER HEART ASSOC BUGHER FDNCTR BIOL MOLECLA JOLLACA UNIV TEXAS MD ANDERSON CANC CTRDEPT MOLEC GENETHOUSTONTX 77030 JOHNS HOPKINS UNIV SCH MEDJOHNS HOPKINS ONCOL CTRBALTIMOREMD 21205 JOHNS HOPKINS UNIV SCH MEDDEPT MEDDIV HEMATOLBALTIMOREMD 21205

Previous studies have documented that 250 bp of the rat cardiac ventricular myosin light-chain 2 (MLC-2v) promoter is sufficient to confer cardiac muscle-specific expression on a luciferase reporter gene in both transgenic mice and primary cultured neonatal rat myocardial cells. Utilizing ligation-mediated PCR to perform in vivo dimethyl sulfate footprinting, the present study has identified protein-DNA interaction within the position from -176 to -165. This region, identified as MLE1, contains a core sequence, CACGTG, which conforms to the consensus E-box site and is identical to the upstream stimulating factor (USF)-binding site of the adenovirus major late promoter. Transient assays of luciferase reporter genes containing point mutations of the site demonstrate the importance of this cis regulatory element in the transcriptional activation of this cardiac muscle gene in ventricular muscle cells. The protein complex that occupies this site is capable of binding to HF-1a and PRE B sites which are known to be required for cardiac muscle-specific expression of rat MLC-2v and alpha-myosin heavy-chain genes, respectively. This study provides direct evidence that USF, a member of the basic helix-loop-helix leucine zipper family, binds to MLE1, HF-1a, and PRE B sites and suggests that it is a component of protein complexes that may coordinately control the expression of MLC-2v and alpha-myosin heavy-chain genes. The current study also provides evidence that USF can positively and negatively regulate the MLC-2v gene via independent cis regulatory elements.

关键词： .myosin regulatory elements luciferase basic helix-loop-helix mle muscle-specific Center for Molecular light-chain MLC promoter Cardiac Ventricular Independent cis

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Expression of aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (Arnt) in adult rabbits known to be non-responsive to cytochrome P-450 1A1 (CYP1A1) inducers

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EUROPEAN JOURNAL OF BIOCHEMISTRY 1996年第3期242卷 512-518页

作者： Takahashi, Y Nakayama, K Shimojima, T Itoh, S Kamataki, T HOKKAIDO UNIV FAC PHARMACEUT SCI DIV DRUG METAB KITA KU SAPPORO HOKKAIDO 060 JAPAN OSAKA UNIV FAC PHARMACEUT SCI DIV BIOMED & IMMUNOL CHEM SUITA OSAKA 565 JAPAN

Induction of aryl hydrocarbon hydroxylase by aryl hydrocarbons occurs only in neonatal rabbits and not in adult rabbits [Kahl, G. F, Friederich, D. E., Bigelow, S. W., Okey, A. B, & Nebert, D. W. (1980) Dev. Pharmacol. Ther. 1, 137-162]. In the present study, we isolated cDNA clones encoding aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (Arnt) from adult rabbits. The deduced amino acid sequences of rabbit AhR and Arnt showed 80% and 94% identities with those of human AhR and Arnt, respectively. Rabbit AhR mRNA was predominantly expressed in the lung and liver. In contrast, rabbit Amt mRNA was expressed at almost the same level in all tissues except for the heart, liver, and small intestine. Gel shift analysis showed that the AhR Amt complex could bind to the consensus xenobiotic-responsive element, which indicates that AhR expressed in adult rabbit livers possessed binding activity to the consensus xenobiotic-responsive element in vitro, although aryl hydrocarbons did not induce the activity of AHH in adult rabbits. We propose that the incapability of adult rabbits to induce cytochrome P-450 1A1 (CYP1A1) is caused by factors other than AhR and Arnt.

关键词： aryl hydrocarbon hydroxylase 3-methylcholanthrene xenobiotic-responsive element basic helix-loop-helix Per-Arnt-Sim domain

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