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Biochem J. Oct 15, 2002; 367(Pt 2): 413–422.
PMCID: PMC1222902

Abundant expression of Dec1/stra13/sharp2 in colon carcinoma: its antagonizing role in serum deprivation-induced apoptosis and selective inhibition of procaspase activation.

Abstract

The basic helix-loop-helix (bHLH) proteins are intimately associated with developmental events such as cell differentiation and lineage commitment. The HLH domain in the bHLH motif is responsible for dimerization, whereas the basic region mediates DNA binding. Based on sequence alignment and domain analysis, differentially expressed in chondrocytes/stimulated with retinoic acid/split and hairy-related proteins (DEC/STRA/SHARPs) represent a new class of bHLH proteins. The present study describes the functional characterization of DEC1. Subtractive experiments and blotting analyses demonstrated that DEC1 was highly expressed in colon carcinomas, but not in the adjacent normal tissues. Several cell cycle blockers markedly induced DEC1 expression. Stable transfectants with a tetracycline-inducible construct demonstrated that DEC1 caused proliferation inhibition, antagonized serum deprivation-induced apoptosis and selectively inhibited the activation of procaspases. These activities were highly correlated with the abundance of tetracycline-induced DEC1. Stable transfectants expressing a mutant DEC1 (lacking the DNA-binding domain) exhibited neither proliferation inhibition nor apoptotic antagonism, which suggests that DNA binding is required for these actions. Enzymic assays and immunoblotting analyses demonstrated that induction of DEC1 by tetracycline significantly decreased the activation of procaspases 3, 7 and 9 but not procaspase 8. The selective suppression on the activation of procaspases 3, 7 and 9 over procaspase 8 suggests that DEC1-mediated anti-apoptosis is achieved by blocking apoptotic pathways initiated via the mitochondria. The results functionally distinguish DEC1 from other bHLH proteins and directly link this factor to oncogenesis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Weintraub H, Davis R, Tapscott S, Thayer M, Krause M, Benezra R, Blackwell TK, Turner D, Rupp R, Hollenberg S, et al. The myoD gene family: nodal point during specification of the muscle cell lineage. Science. 1991 Feb 15;251(4995):761–766. [PubMed]
  • Villares R, Cabrera CV. The achaete-scute gene complex of D. melanogaster: conserved domains in a subset of genes required for neurogenesis and their homology to myc. Cell. 1987 Jul 31;50(3):415–424. [PubMed]
  • Bissonnette RP, McGahon A, Mahboubi A, Green DR. Functional Myc-Max heterodimer is required for activation-induced apoptosis in T cell hybridomas. J Exp Med. 1994 Dec 1;180(6):2413–2418. [PMC free article] [PubMed]
  • Cronmiller C, Schedl P, Cline TW. Molecular characterization of daughterless, a Drosophila sex determination gene with multiple roles in development. Genes Dev. 1988 Dec;2(12A):1666–1676. [PubMed]
  • Beckmann H, Su LK, Kadesch T. TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev. 1990 Feb;4(2):167–179. [PubMed]
  • Nikoloff DM, McGraw P, Henry SA. The INO2 gene of Saccharomyces cerevisiae encodes a helix-loop-helix protein that is required for activation of phospholipid synthesis. Nucleic Acids Res. 1992 Jun 25;20(12):3253–3253. [PMC free article] [PubMed]
  • Hirose K, Morita M, Ema M, Mimura J, Hamada H, Fujii H, Saijo Y, Gotoh O, Sogawa K, Fujii-Kuriyama Y. cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt). Mol Cell Biol. 1996 Apr;16(4):1706–1713. [PMC free article] [PubMed]
  • Massari ME, Murre C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol. 2000 Jan;20(2):429–440. [PMC free article] [PubMed]
  • Murre C, Bain G, van Dijk MA, Engel I, Furnari BA, Massari ME, Matthews JR, Quong MW, Rivera RR, Stuiver MH. Structure and function of helix-loop-helix proteins. Biochim Biophys Acta. 1994 Jun 21;1218(2):129–135. [PubMed]
  • Boudjelal M, Taneja R, Matsubara S, Bouillet P, Dolle P, Chambon P. Overexpression of Stra13, a novel retinoic acid-inducible gene of the basic helix-loop-helix family, inhibits mesodermal and promotes neuronal differentiation of P19 cells. Genes Dev. 1997 Aug 15;11(16):2052–2065. [PMC free article] [PubMed]
  • Fujimoto K, Shen M, Noshiro M, Matsubara K, Shingu S, Honda K, Yoshida E, Suardita K, Matsuda Y, Kato Y. Molecular cloning and characterization of DEC2, a new member of basic helix-loop-helix proteins. Biochem Biophys Res Commun. 2001 Jan 12;280(1):164–171. [PubMed]
  • Rossner MJ, Dörr J, Gass P, Schwab MH, Nave KA. SHARPs: mammalian enhancer-of-split- and hairy-related proteins coupled to neuronal stimulation. Mol Cell Neurosci. 1997;9(5-6):460–475. [PubMed]
  • Shen M, Kawamoto T, Yan W, Nakamasu K, Tamagami M, Koyano Y, Noshiro M, Kato Y. Molecular characterization of the novel basic helix-loop-helix protein DEC1 expressed in differentiated human embryo chondrocytes. Biochem Biophys Res Commun. 1997 Jul 18;236(2):294–298. [PubMed]
  • Fisher AL, Ohsako S, Caudy M. The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain. Mol Cell Biol. 1996 Jun;16(6):2670–2677. [PMC free article] [PubMed]
  • Giebel B, Campos-Ortega JA. Functional dissection of the Drosophila enhancer of split protein, a suppressor of neurogenesis. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6250–6254. [PMC free article] [PubMed]
  • Poortinga G, Watanabe M, Parkhurst SM. Drosophila CtBP: a Hairy-interacting protein required for embryonic segmentation and hairy-mediated transcriptional repression. EMBO J. 1998 Apr 1;17(7):2067–2078. [PMC free article] [PubMed]
  • Chen G, Fernandez J, Mische S, Courey AJ. A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development. Genes Dev. 1999 Sep 1;13(17):2218–2230. [PMC free article] [PubMed]
  • Hojo M, Ohtsuka T, Hashimoto N, Gradwohl G, Guillemot F, Kageyama R. Glial cell fate specification modulated by the bHLH gene Hes5 in mouse retina. Development. 2000 Jun;127(12):2515–2522. [PubMed]
  • Ohtsuka T, Sakamoto M, Guillemot F, Kageyama R. Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. J Biol Chem. 2001 Aug 10;276(32):30467–30474. [PubMed]
  • Sun H, Taneja R. Stra13 expression is associated with growth arrest and represses transcription through histone deacetylase (HDAC)-dependent and HDAC-independent mechanisms. Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4058–4063. [PMC free article] [PubMed]
  • Sun H, Lu B, Li RQ, Flavell RA, Taneja R. Defective T cell activation and autoimmune disorder in Stra13-deficient mice. Nat Immunol. 2001 Nov;2(11):1040–1047. [PubMed]
  • Garriga-Canut M, Roopra A, Buckley NJ. The basic helix-loop-helix protein, sharp-1, represses transcription by a histone deacetylase-dependent and histone deacetylase-independent mechanism. J Biol Chem. 2001 May 4;276(18):14821–14828. [PubMed]
  • Ivanova AV, Ivanov SV, Danilkovitch-Miagkova A, Lerman MI. Regulation of STRA13 by the von Hippel-Lindau tumor suppressor protein, hypoxia, and the UBC9/ubiquitin proteasome degradation pathway. J Biol Chem. 2001 May 4;276(18):15306–15315. [PubMed]
  • Zawel Leigh, Yu Jian, Torrance Christopher J, Markowitz Sanford, Kinzler Kenneth W, Vogelstein Bert, Zhou Shibin. DEC1 is a downstream target of TGF-beta with sequence-specific transcriptional repressor activities. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2848–2853. [PMC free article] [PubMed]
  • Hu M, Yan B. Isolation of multiple distinct cDNAs by a single cDNA-trapping procedure. Anal Biochem. 1999 Jan 15;266(2):233–235. [PubMed]
  • Zhang H, LeCulyse E, Liu L, Hu M, Matoney L, Zhu W, Yan B. Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation. Arch Biochem Biophys. 1999 Aug 1;368(1):14–22. [PubMed]
  • Zhu W, Song L, Zhang H, Matoney L, LeCluyse E, Yan B. Dexamethasone differentially regulates expression of carboxylesterase genes in humans and rats. Drug Metab Dispos. 2000 Feb;28(2):186–191. [PubMed]
  • Yan B, Yang D, Bullock P, Parkinson A. Rat serum carboxylesterase. Cloning, expression, regulation, and evidence of secretion from liver. J Biol Chem. 1995 Aug 11;270(32):19128–19134. [PubMed]
  • Cryns V, Yuan J. Proteases to die for. Genes Dev. 1998 Jun 1;12(11):1551–1570. [PubMed]
  • Lüscher B, Eisenman RN. New light on Myc and Myb. Part I. Myc. Genes Dev. 1990 Dec;4(12A):2025–2035. [PubMed]
  • Packham G, Cleveland JL. The role of ornithine decarboxylase in c-Myc-induced apoptosis. Curr Top Microbiol Immunol. 1995;194:283–290. [PubMed]
  • Penn LJ, Laufer EM, Land H. C-MYC: evidence for multiple regulatory functions. Semin Cancer Biol. 1990 Feb;1(1):69–80. [PubMed]
  • Condorelli GL, Tocci A, Botta R, Facchiano F, Testa U, Vitelli L, Valtieri M, Croce CM, Peschle C. Ectopic TAL-1/SCL expression in phenotypically normal or leukemic myeloid precursors: proliferative and antiapoptotic effects coupled with a differentiation blockade. Mol Cell Biol. 1997 May;17(5):2954–2969. [PMC free article] [PubMed]
  • Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH, Hannon GJ. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999 Sep 1;13(17):2207–2217. [PMC free article] [PubMed]
  • Norton JD. ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J Cell Sci. 2000 Nov;113(Pt 22):3897–3905. [PubMed]
  • Kim D, Peng XC, Sun XH. Massive apoptosis of thymocytes in T-cell-deficient Id1 transgenic mice. Mol Cell Biol. 1999 Dec;19(12):8240–8253. [PMC free article] [PubMed]
  • Wice BM, Gordon JI. Forced expression of Id-1 in the adult mouse small intestinal epithelium is associated with development of adenomas. J Biol Chem. 1998 Sep 25;273(39):25310–25319. [PubMed]
  • Shen M, Kawamoto T, Teramoto M, Makihira S, Fujimoto K, Yan W, Noshiro M, Kato Y. Induction of basic helix-loop-helix protein DEC1 (BHLHB2)/Stra13/Sharp2 in response to the cyclic adenosine monophosphate pathway. Eur J Cell Biol. 2001 May;80(5):329–334. [PubMed]
  • Baek JH, Jang JE, Kang CM, Chung HY, Kim ND, Kim KW. Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene. 2000 Sep 21;19(40):4621–4631. [PubMed]
  • Vaupel P, Kelleher DK, Höckel M. Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol. 2001 Apr;28(2 Suppl 8):29–35. [PubMed]
  • Yu JL, Rak JW, Carmeliet P, Nagy A, Kerbel RS, Coomber BL. Heterogeneous vascular dependence of tumor cell populations. Am J Pathol. 2001 Apr;158(4):1325–1334. [PMC free article] [PubMed]

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