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HERP, a new primary target of notch regulated by ligand binding

MOLECULAR AND CELLULAR BIOLOGY 2001年第17期21卷 6071-6079页

作者： Iso, T Sartorelli, V Chung, G Shichinohe, T Kedes, L Hamamori, Y Univ So Calif Keck Sch Med Inst Med Genet Los Angeles CA 90089 USA Univ So Calif Keck Sch Med Dept Biochem & Mol Biol Los Angeles CA 90089 USA Univ So Calif Keck Sch Med Dept Pathol Los Angeles CA 90089 USA Univ So Calif Keck Sch Med Dept Med Los Angeles CA 90089 USA NIAMS Muscle Biol Lab Muscle Gene Express Grp IRPNIH Bethesda MD 20892 USA

Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis in metazoans. Ligand binding initiates the signal through regulated intramembrane proteolysis of a transmembrane Notch receptor which releases the signal-transducing Notch intracellular domain (NICD). The HES/E(spl) gene family is a primary target of Notch and thus far the only known Notch effector. A newly isolated HER-P family, a HES-related basic helix-loop-helix protein family, has been proposed as a potential target of Notch, based on its induction following NICD overexpression. However, NICD is physiologically maintained at an extremely low level that typically escapes detection, and therefore, nonregulated overexpression of NICD-as in transient transfection-has the potential of generating cellular responses of little physiological relevance. Indeed, a constitutively active NICD indiscriminately up-regulates expression of both HERP1 and HERP2 mRNAs. However, physiological Notch stimulation through ligand binding results in the selective induction of HERP2 but not HERP1 mRNA and causes only marginal up-regulation of HES1 mRNA. Importantly, HERP2 is an immediate target gene of Notch signaling since HERP2 mRNA expression is induced even in the absence of de novo protein synthesis. HERP2 mRNA induction is accompanied by specific expression of HERP2 protein in the nucleus. Furthermore, using RBP-jk-deficient cells, we show that an RBP-Jk protein, a transcription factor that directly activates HES/E(spl) transcription, also is essential for HERP2 mRNA expression and that expression of exogenous RBP-jk is sufficient to rescue HERP2 mRNA expression. These data establish that HERP2 is a novel primary target gene of Notch that, together with HES, may effect diverse biological activities of Notch.

关键词： .Notch Signaling basic helix-loop-helix NICD Notch Receptor primary target regulated intramembrane HES spl

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Spz1, a novel bHLH-Zip protein, is specifically expressed in testis

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MECHANISMS OF DEVELOPMENT 2001年第2期100卷 177-187页

作者： Hsu, SH Shyu, HW Hsieh-Li, HM Li, H Acad Sinica Inst Mol Biol Taipei 11529 Taiwan Natl Def Med Ctr Inst Life Sci Taipei Taiwan Taipei Med Coll Inst Med Sci Taipei Taiwan

We isolated a novel bHLH-Zip gene designated Spz1 from a mouse testis cDNA library. Spz1 is expressed specifically in the testis and epididymis. Immunofluorescence staining detected Spz1 protein in the nuclei of LFG6 Leydig cells. The ability of Spz1 protein to bind to the bHLH consensus-binding site, the E-box, was confirmed by EMSA, and a 9-bp asymmetric target site was identified by random selection and PCR amplification. Hormonal regulation of Spz1 was investigated and downregulation of Spz1 expression by testosterone and retinoic acid was found. This nuclear transcription factor may play a crucial role in spermatogenesis by regulating cell proliferation or differentiation through binding to specific DNA sequences like other bHLH-Zip molecules. (C) 2001 Elsevier Science Ireland Ltd. Ail rights reserved.

关键词： basic helix-loop-helix leucine zipper mouse spermatogenesis testis

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Pod-1/Capsulin shows a sex- and stage-dependent expression pattern in the mouse gonad development and represses expression of Ad4BP/SF-1

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MECHANISMS OF DEVELOPMENT 2001年第1-2期102卷 135-144页

作者： Tamura, M Kanno, Y Chuma, S Saito, T Nakatsuji, N Natl Inst Genet Genet Strains Res Ctr Mammalian Dev Lab Mishima Shizuoka 411 Japan Saitama Univ Fac Sci Dept Biol Urawa Saitama 338 Japan Kyoto Univ Inst Frontier Med Sci Dept Dev & Differentiat Sakyo Ku Kyoto 6068507 Japan

Mammalian sex-determination and differentiation are controlled by several genes, such as Sry, Sox-9, Dax-1 and Mullarian inhibiting substance (MIS), but their upstream and downstream genes are largely unknown. Ad4BP/SF-1, encoding a zinc finger transcription factor, plays important roles in gonadogenesis. Disruption of this gene caused disappearance of the urogenital system including the gonad. Ad4BP/ SF-1, however, is also involved in the sex differentiation of the gonad at later stages, such as the regulation of steroid hormones and MIS. Pod-1/Capsulin, a member of basic helix-loop-helix transcription factors, is expressed in a pattern closely related but mostly complimentary to that of the Ad4BP/SF-1 expression in the developing gonad. In the co-transfection experiment using cultured cells, overexpression of Pod-1/Capsulin repressed expression of a reporter gene that carried the upstream regulatory region of the Ar4BP/SF-1 gene. Furthermore, forced expression of Pod-1/Capsulin repressed expression of Ad4BP/SF-1 in the Leydig cell derived I-10 cells. These results suggest that Pod-1/Capsulin may play important roles in the development and sex differentiation of the mammalian gonad via transcriptional regulation of Ad4BP/SF-1. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

关键词： sex differentiation gonad development basic helix-loop-helix Pod-1/Capsulin Ad4BP/SF-1

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Cytokine response gene 8 (CR8) regulates the cell cycle G1-S phase transition and promotes cellular survival

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ONCOGENE 2001年第14期20卷 1771-1783页

作者： Beadling, C Cereseto, A Fan, W Naramura, M Smith, KA New York Presbyterian Cornell Med Ctr Div Immunol Dept Med New York NY 10021 USA New York Presbyterian Cornell Med Ctr Weill Med Coll New York NY 10021 USA New York Presbyterian Cornell Med Ctr Grad Sch Med Sci New York NY 10021 USA

Cellular proliferation and survival are modulated by the expression of specific genes. Cytokine response gene 8 (CR8), which was originally cloned as an IL-2-induced gene in human T lymphocytes, encodes a basic helix-loop-helix (bHLH) transcription factor, The CR8 gene product is highly conserved among human, mouse and rat, and contains sequence motifs that distinguish it from other bHLH families, The CR8 gene is ubiquitously expressed, and CR8 gene expression is induced by both growth-promoting as well as growth-inhibitory stimuli. As bHLH proteins have been found to regulate both the G1-S phase cell cycle transition, as well as cellular survival, the effects of CR8 on these processes were investigated. Ectopic CR8 expression in asynchronous U2OS cell cultures reduces the percentage of cells in the cell cycle S phase, and also slows the entry of G1-synchronized cells into S phase. The prolonged G1 interval correlates with impaired elevation of cyclin E protein and prolonged p21 protein expression in G1, CR8 expression also protects U2OS cells from serum-withdrawal induced apoptosis, These results indicate that CR8 is an important modulator of both the G1-S phase cell cycle transition, and cellular survival.

关键词： basic helix-loop-helix G1 progression survival

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Cloning and characterization of the Xenopus laevis p8 gene

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DEVELOPMENT GROWTH & DIFFERENTIATION 2001年第6期43卷 693-698页

作者： Igarashi, T Kuroda, H Takahashi, S Asashima, M Univ Tokyo Dept Life Sci Biol Meguro Ku Tokyo 1538902 Japan Univ Tokyo Grad Sch Arts & Sci Meguro Ku Tokyo 1538902 Japan

The p8 gene encodes a transcription factor with a basic helix-loop-helix motif and has been cloned in rat, mouse and human. It is upregulated in acute pancreatitis. In the present study, the Xenopus laevis homolog of p8 (Xp8) was isolated by PCR. The full-length Xp8 cDNA consists of 677 bp and encodes 82 amino acids. The basic helix-loop-helix region is well conserved between X. laevis and mammals, Overexpression of an Xp8-EGFP fusion protein indicated that Xp8 was localized to nucleus, as in mammals. Analysis by RT-PCR showed that expression of Xp8 was increased after gastrulation and maintained into later developmental stages. Expression was detected in the prospective neural region at the neurula stage by whole-mount in situ hybridization. At the larval stage, Xp8 was expressed in central nervous regions, such as ventrolateral brain, trigeminal nerve, vestibulocochlear nerve and dorsal neural tube. Expression was also detected in the basal cement gland, olfactory placode, ear vesicle, notochord and anus. This specific pattern of expression suggests that Xp8 may play a role in the development of the central nervous system in X. laevis.

关键词： basic helix-loop-helix development nerve p8 Xenopus

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Early patterning of the prospective midbrain-hindbrain boundary by the HES-related gene XHR1 in Xenopus embryos

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MECHANISMS OF DEVELOPMENT 2001年第2期109卷 225-239页

作者： Shinga, J Itoh, M Shiokawa, K Taira, S Taira, M Univ Tokyo Grad Sch Sci Dept Biol Sci Bunkyo Ku Tokyo 1130033 Japan Japan Sci & Technol Corp CREST Kawaguchi Saitama 3320012 Japan

The molecular mechanisms that govern early patterning of anterior neuroectoderm (ANE) for the prospective brain region in vertebrates are largely unknown. Screening a cDNA library of Xenopus ANE led to the isolation of a Hairy and Enhancer of split- (HES)-related transcriptional repressor gene. Xenopus HES-related 1 (XHR1). XHR1 is specifically expressed in the midbrain-hindbrain boundary (MHB) region at the tailbud stage. The localized expression of XHR1 was detected as early as the early gastrula stage in the presumptive MHB region, an area just anterior to the involuting dorsal mesoderm that is demarcated by the expression of the gene Xbra. Expression of XHR1 was detected much earlier than that of other known MHB genes, XPav-2 and En-2, and also before the formation of the expression boundary between Xotx2 and Xgbx-2, suggesting that the early patterning of the presumptive MHB is independent of Xotx2 and Xgbx-2. Instead, the location of XHR1 expression appears to be determined in relation to the Xbra expression domain, since reduced or ectopic expression of Xbra altered the XHR1 expression domain according to the location of Xbra expression. In functional assays using mRNA injection, overexpression of dominant-negative forms of XHR1 in the MHB region led to marked reduction of XPax-2 and En-2 expression, and this phenotype was rescued by coexpression of wild-type XHR1. Furthermore, ectopically expressed wild-type XHR1 near the MHB region enhanced En-2 expression only in the MHB region but not in the region outside the MHB. These data suggest that XHR1 is required, but not sufficient by itself, to initiate MHB marker gene expression. Based on these data, we propose that XHR1 demarcates the prospective MHB region in the neuroectoderm in Xenopus early gastrulae. (C) 2001 Elsevier Science Ltd. All rights reserved.

关键词： Xenopus neuroectoderm central nervous systems patterning midbrain-hindbrain boundary basic helix-loop-helix hairy enhancer of split HES Xenopus HES-related 1

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Common regulation of growth arrest and differentiation of osteoblasts by helix-loop-helix factors

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MOLECULAR AND CELLULAR BIOLOGY 2001年第21期21卷 7416-7428页

作者： Funato, N Ohtani, K Ohyama, K Kuroda, T Nakamura, M Tokyo Med & Dent Univ Human Gene Sci Ctr Bunkyo Ku Tokyo 1138510 Japan

Cellular differentiation entails the coordination of cell cycle arrest and tissue-specific gene expression. We investigated the involvement of basic helix-loop-helix (bHLH) factors in differentiation of osteoblasts using the human osteoblastic cell line MG63. Serum starvation induced growth arrest at G, phase, accompanied by expression of cyclin-dependent kinase inhibitor p21(WAF1/Cip1). Reporter assays with the p21 gene promoter demonstrated that the combination of E2A (E12 or E47) and coactivator CBP was responsible for p21 induction independent of p53. Twist inhibited E2A-CBP-dependent activation of the exogenous and endogenous p21 promoters. Ids similarly inhibited the exogenously transfected p21 promoter;however less antagonistic effect on the endogenous p21 promoter was observed. Twist was predominantly present in nuclei in MG63 cells growing in complete medium, while it localized mainly in the cytoplasm after serum starvation. The fibroblast growth factor receptor 3 gene (FGFR3), which generates signals leading to differentiation of osteoblasts, was found to be controlled by the same transcriptional regulation as the p21 gene. E2A and Twist influenced alkaline phosphatase expression, a consensus marker of osteoblast differentiation. Expression of E2A and FGFR3 was seen at the location of osteoblast differentiation in the calvaria of mouse embryos, implicating bHLH molecules in physiological osteoblast differentiation. These results demonstrate that a common regulatory system is involved in at least two distinct steps in osteoblastic differentiation. Our results also provide the molecular basis of Saethre-Chotzen syndrome, caused by mutations of the TWIST and FGFR3 genes.

关键词： .MG cells bHLH basic helix-loop-helix CBP Serum Starvation Differentiation of Osteoblasts

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bHLH transcription factor MyoD affects myosin heavy chain expression pattern in a muscle-specific fashion

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AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 2001年第2期280卷 C408-C413页

作者： Seward, DJ Haney, JC Rudnicki, MA Swoap, SJ Williams Coll Dept Biol Williamstown MA 01267 USA Ottawa Gen Hosp Res Inst Program Mol Genet Ottawa ON K1H 8L6 Canada

A strong correlative pattern between MyoD gene expression and myosin heavy chain IIB (MHC IIB) gene expression exists. To test whether this correlative relationship is causative, MHC gene expression in muscles from MyoD(-/-) mice was analyzed. The MHC IIB gene was not detectable in the MyoD(-/-) diaphragm, whereas the MHC IIB protein made up 10.0 +/- 1.7% of the MHC protein pool in the wild-type (WT) mouse diaphragm. Furthermore, the MHC IIA protein was not detectable in the MyoD(-/-) biceps brachii, and the MHC IIB protein was overexpressed in the masseter. To examine whether MyoD is required for the upregulation of the MHC IIB gene within slow muscle after disuse, MyoD(-/-) and WT hindlimb musculature was unweighted. MyoD(-/-) exhibited a diminished response in the upregulation of the MHC IIB mRNA within the soleus muscle as a result of the hindlimb unweighting. Collectively, these data suggest that MyoD plays a role in the MHC profile in a muscle-specific fashion.

关键词： basic helix-loop-helix fiber type transcription factor myogenic regulatory factor

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Vitamin D₃ enhances the expression of I-mfa, an inhibitor of the MyoD family, in osteoblasts

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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2001年第1-2期1539卷 122-130页

作者： Tsuji, K Kraut, N Groudine, M Noda, M Tokyo Med & Dent Univ Med Res Inst Dept Mol Pharmacol Chiyoda Ku Tokyo 1010062 Japan Boehringer Ingelheim Pharma KG Genom Grp Ingelheim Germany Fred Hutchinson Canc Res Ctr Seattle WA 98104 USA Univ Washington Sch Med Dept Radiat Oncol Seattle WA 98195 USA

I-mfa (inhibitor of the MyoD family) is a transcription modulator that binds to and suppresses the transcriptional activity of MyoD family members. I-mfa transcripts are expressed in sclerotome, suggesting a role of I-mfa in skeletogenesis. The aim of this study was to examine the expression and regulation of I-mfa in osteoblasts. We found that I-mfa is expressed at a low level in an osteoblast-like cell line, MC3T3E1, and a pluripotent differentiation modulator, 1,25-dihydroxyvitamin D-3, specifically enhanced I-mfa mRNA expression. This effect was completely blocked by the presence of an RNA polymerase inhibitor, but not by a protein synthesis inhibitor, suggesting that 1,25-dihydroxyvitamin D3 upregulates transcription of the I-mfa gene without requirement for new protein synthesis. Western blot analysis indicated that 1,25-dihydroxyvitamin D3 increased the I-mfa protein levels severalfold in MC3T3E1 cells. I-mfa expression was also observed in primary mouse calvaria cells and ROS17/2.8 cells and 1.25-dihydroxyvitamin D3 enhanced I-mfa expression in these cells. These data indicate that I-mfa is a novel transcriptional regulator gene expressed in osteoblasts and that its level is under the control of 1,1.25-dihydroxyvitamin D-3. (C) 2001 Elsevier Science B.V. All rights reserved.

关键词： inhibitor of MyoD family A basic helix-loop-helix 1,25-dihydroxyvitamin D-3 osteoblast

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Variants of neurogenin 3 gene are not associated with Type II diabetes in Japanese subjects

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DIABETOLOGIA 2001年第2期44卷 241-244页

作者： Okada, T Tobe, K Hara, K Yasuda, K Kawaguchi, Y Ikegami, H Ito, C Kadowaki, T Univ Tokyo Grad Sch Med Dept Metab Dis Tokyo Japan Chiba Univ Sch Med Dept Med Genet Chiba 280 Japan Osaka Univ Sch Med Dept Geriatr Med Osaka 553 Japan Hiroshima Atom Bomb Casualty Council Hlth Managem Hiroshima Japan

Aims/hypothesis. Neurogenin 3 (ngn3) is a transcription factor expressed in the endocrine precursor cells of the pancreas. It has recently been reported that ngn3-deficient mice show absence of pancreatic endocrine cells and die of postnatal diabetes. The purpose of this investigation was to screen for polymorphisms of the ngn3 gene and to test whether these polymorphisms are associated with Type II (non-insulin-dependent) diabetes mellitus in the Japanese subjects. Methods. We screened ngn3 gene and upstream region by direct sequencing and estimated the prevalence of polymorphisms in 197 patients with Type II (non-insulin-dependent) diabetes mellitus and 216 control subjects. Results. We identified four novel polymorphisms, Ser199Phe (596C/T), -43insCA, -983C/T and -1822G/A. In an association study the allelic frequencies of the major allele of these four polymorphisms were 0.721, 0.914, 0.912 and 0.530 in diabetic patients, respectively, and 0.694, 0.905, 0.917 and 0.537 in control subjects, respectively. Conclusion/interpretation. Mutations and polymorphisms of ngn3 gene are not significantly associated with Type II (non-insulin-dependent) diabetes mellitus in the Japanese subjects.

关键词： neurogenin 3 transcription factor Type II diabetes mellitus polymorphisms basic helix-loop-helix

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