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WS5, a direct target of oncogenic transcription factor Myc, is related to human melanoma glycoprotein genes and has oncogenic potential

Oncogene volume 26, pages 1769–1779 (2007)Cite this article

Abstract

We have isolated a gene (WS5) that is specifically expressed at the mRNA and protein level in avian fibroblasts transformed by the v-myc oncogene of avian acute leukemia virus MC29. In a conditional cell transformation system, WS5 gene expression was tightly correlated with v-myc activation. The WS5 gene contains 11 exons, encoding a 733-amino acid protein with a transmembrane region and a polycystic kidney disease (PKD) domain. Near the transcriptional start site, the WS5 promoter contains a cluster of four binding sites for the Myc–Max complex and a binding site for transcription factor C/EBPα. Electrophoretic mobility shift assays and chromatin immunoprecipitation showed that Myc, Max and C/EBPα bind specifically to these sites. Functional promoter analyses revealed that both the Myc-binding site cluster and the C/EBPα-binding site are essential for strong transcriptional activation, and that Myc and C/EBPα synergistically activate the WS5 promoter. Ectopic expression of WS5 led to cell transformation documented by anchorage-independent growth. The human melanoma antigen Pmel17, a type I transmembrane glycoprotein, is the mammalian protein with the highest amino acid sequence identity (38%) to WS5. The Pmel17 gene is regulated by the MITF protein, a bHLHZip transcription factor with DNA binding specificities similar to those of Myc/Max. WS5 is also related to human glycoprotein GPNMB expressed in metastatic melanoma cells and implicated in the progression of brain and liver tumors.

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References

  • Adhikary S, Eilers M . (2005). Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 6: 635–645.

    Article  CAS  Google Scholar 

  • Bader AG, Hartl M, Bister K . (2000). Conditional cell transformation by doxycycline-controlled expression of the ASV17 v-jun allele. Virology 270: 98–110.

    Article  CAS  Google Scholar 

  • Ben-Porath I, Yanuka O, Benvenisty N . (1999). The Tmp gene, encoding a membrane protein, is a c-Myc target with a tumorigenic activity. Mol Cell Biol 19: 3529–3539.

    Article  CAS  Google Scholar 

  • Berson JF, Harper DC, Tenza D, Raposo G, Marks MS . (2001). Pmel17 initiates premelanosome morphogenesis within multivesicular bodies. Mol Biol Cell 12: 3451–3464.

    Article  CAS  Google Scholar 

  • Berson JF, Theos AC, Harper DC, Tenza D, Raposo G, Marks MS . (2003). Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis. J Cell Biol 161: 521–533.

    Article  CAS  Google Scholar 

  • Bister K, Hayman MJ, Vogt PK . (1977). Defectiveness of avian myelocytomatosis virus MC29: isolation of long-term nonproducer cultures and analysis of virus-specific polypeptide synthesis. Virology 82: 431–448.

    Article  CAS  Google Scholar 

  • Bister K, Jansen HW . (1986). Oncogenes in retroviruses and cells: biochemistry and molecular genetics. Adv Cancer Res 47: 99–188.

    Article  CAS  Google Scholar 

  • Blackwell TK, Huang J, Ma A, Kretzner L, Alt FW, Eisenman RN et al. (1993). Binding of Myc proteins to canonical and noncanonical DNA sequences. Mol Cell Biol 13: 5216–5224.

    Article  CAS  Google Scholar 

  • Bycroft M, Bateman A, Clarke J, Hamill SJ, Sandford R, Thomas RL et al. (1999). The structure of a PKD domain from polycystin-1: implications for polycystic kidney disease. EMBO J 18: 297–305.

    Article  CAS  Google Scholar 

  • Clark LA, Wahl JM, Rees CA, Murphy KE . (2006). Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proc Natl Acad Sci USA 103: 1376–1381.

    Article  CAS  Google Scholar 

  • Dang CV . (1999). c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19: 1–11.

    Article  CAS  Google Scholar 

  • Du J, Miller AJ, Widlund HR, Horstmann MA, Ramaswamy S, Fisher DE . (2003). MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma. Am J Pathol 163: 333–343.

    Article  CAS  Google Scholar 

  • Eisenman RN . (2001). Deconstructing Myc. Genes Dev 15: 2023–2030.

    Article  CAS  Google Scholar 

  • Ferré-D'Amaré AR, Prendergast GC, Ziff EB, Burley SK . (1993). Recognition by Max of its cognate DNA through a dimeric b/HLH/Z domain. Nature 363: 38–46.

    Article  Google Scholar 

  • Fieber W, Schneider ML, Matt T, Kräutler B, Konrat R, Bister K . (2001). Structure, function, and dynamics of the dimerization and DNA binding domain of oncogenic transcription factor v-Myc. J Mol Biol 307: 1395–1410.

    Article  CAS  Google Scholar 

  • Grabe N . (2002). AliBaba2: context specific identification of transcription factor binding sites. In Silico Biol 2: S1–15.

    PubMed  Google Scholar 

  • Grandori C, Cowley SM, James LP, Eisenman RN . (2000). The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu Rev Cell Dev Biol 16: 653–699.

    Article  CAS  Google Scholar 

  • Hartl M, Bister K . (1995). Specific activation in jun-transformed avian fibroblasts of a gene (bkj) related to the avian β-keratin gene family. Proc Natl Acad Sci USA 92: 11731–11735.

    Article  CAS  Google Scholar 

  • Hartl M, Bister K . (1998). Structure and transcriptional regulation of BKJ, a novel AP-1 target gene activated during jun- or fos-induced fibroblast transformation. Oncogene 17: 2901–2913.

    Article  CAS  Google Scholar 

  • Hartl M, Karagiannidis AI, Bister K . (2006). Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activation of genes implicated in cell motility and metastasis. Oncogene 25: 4043–4055.

    Article  CAS  Google Scholar 

  • Hartl M, Matt T, Schüler W, Siemeister G, Kontaxis G, Kloiber K et al. (2003). Cell transformation by the v-myc oncogene abrogates c-Myc/Max-mediated suppression of a C/EBPβ-dependent lipocalin gene. J Mol Biol 333: 33–46.

    Article  CAS  Google Scholar 

  • Hartl M, Reiter F, Bader AG, Castellazzi M, Bister K . (2001). JAC, a direct target of oncogenic transcription factor Jun, is involved in cell transformation and tumorigenesis. Proc Natl Acad Sci USA 98: 13601–13606.

    Article  CAS  Google Scholar 

  • Heckman CA, Wheeler MA, Boxer LM . (2003). Regulation of Bcl-2 expression by C/EBP in t(14;18) lymphoma cells. Oncogene 22: 7891–7899.

    Article  Google Scholar 

  • Hermeking H, Rago C, Schuhmacher M, Li Q, Barrett JF, Obaya AJ et al. (2000). Identification of CDK4 as a target of c-MYC. Proc Natl Acad Sci USA 97: 2229–2234.

    Article  CAS  Google Scholar 

  • Jing H, Takagi J, Liu JH, Lindgren S, Zhang RG, Joachimiak A et al. (2002). Archaeal surface layer proteins contain β propeller, PKD, and β helix domains and are related to metazoan cell surface proteins. Structure 10: 1453–1464.

    Article  CAS  Google Scholar 

  • Kato GJ, Dang CV . (1992). Function of the c-Myc oncoprotein. FASEB J 6: 3065–3072.

    Article  CAS  Google Scholar 

  • Kwon BS, Chintamaneni C, Kozak CA, Copeland NG, Gilbert DJ, Jenkins N et al. (1991). A melanocyte-specific gene, Pmel 17, maps near the silver coat color locus on mouse chromosome 10 and is in a syntenic region on human chromosome 12. Proc Natl Acad Sci USA 88: 9228–9232.

    Article  CAS  Google Scholar 

  • Levens DL . (2003). Reconstructing MYC. Genes Dev 17: 1071–1077.

    Article  CAS  Google Scholar 

  • Liu YN, Kang BB, Chen JH . (2004). Transcriptional regulation of human osteopontin promoter by C/EBPα and AML-1 in metastatic cancer cells. Oncogene 23: 278–288.

    Article  CAS  Google Scholar 

  • Matys V, Fricke E, Geffers R, Gößling E, Haubrock M, Hehl R et al. (2003). TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 31: 374–378.

    Article  CAS  Google Scholar 

  • Menssen A, Hermeking H . (2002). Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes. Proc Natl Acad Sci USA 99: 6274–6279.

    Article  CAS  Google Scholar 

  • Mink S, Mutschler B, Weiskirchen R, Bister K, Klempnauer KH . (1996). A novel function for Myc: inhibition of C/EBP-dependent gene activation. Proc Natl Acad Sci USA 93: 6635–6640.

    Article  CAS  Google Scholar 

  • Mink S, Jaswal S, Burk O, Klempnauer KH . (1999). The v-Myb oncoprotein activates C/EBPβ expression by stimulating an autoregulatory loop at the C/EBPβ promoter. Biochim Biophys Acta 1447: 175–184.

    Article  CAS  Google Scholar 

  • Mochii M, Agata K, Eguchi G . (1991). Complete sequence and expression of a cDNA encoding a chicken 115-kDa melanosomal matrix protein. Pigment Cell Res 4: 41–47.

    Article  CAS  Google Scholar 

  • Nair SK, Burley SK . (2003). X-ray structures of Myc-Max and Mad-Max recognizing DNA: molecular bases of regulation by proto-oncogenic transcription factors. Cell 112: 193–205.

    Article  CAS  Google Scholar 

  • Neiman PE, Ruddell A, Jasoni C, Loring G., Thomas SJ, Brandvold KA et al. (2001). Analysis of gene expression during myc oncogene-induced lymphomagenesis in the bursa of Fabricius. Proc Natl Acad Sci USA 98: 6378–6383.

    Article  CAS  Google Scholar 

  • Nesbit CE, Tersak JM, Prochownik EV . (1999). MYC oncogenes and human neoplastic disease. Oncogene 18: 3004–3016.

    Article  CAS  Google Scholar 

  • Oberst C, Hartl M, Weiskirchen R, Bister K . (1999). Conditional cell transformation by doxycycline-controlled expression of the MC29 v-myc allele. Virology 253: 193–207.

    Article  CAS  Google Scholar 

  • O'Donnell KA, Yu D, Zeller KI, Kim JW, Racke F, Thomas-Tikhonenko A et al. (2006). Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis. Mol Cell Biol 26: 2373–2386.

    Article  CAS  Google Scholar 

  • Patel JH, Loboda AP, Showe MK, Showe LC, McMahon SB . (2004). Analysis of genomic targets reveals complex functions of MYC. Nat Rev Cancer 4: 562–568.

    Article  CAS  Google Scholar 

  • Rich JN, Shi Q, Hjelmeland M, Cummings TJ, Kuan CT, Bigner DD et al. (2003). Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem 278: 15951–15957.

    Article  CAS  Google Scholar 

  • Secombe J, Pierce SB, Eisenman RN . (2004). Myc: A weapon of mass destruction. Cell 117: 153–156.

    Article  CAS  Google Scholar 

  • Theos AC, Truschel ST, Raposo G, Marks MS . (2005). The Silver locus product Pmel17/gp100/Silv/ME20: controversial in name and in function. Pigment Cell Res 18: 322–336.

    Article  CAS  Google Scholar 

  • Turque N, Denhez F, Martin P, Planque N, Bailly M, Bègue A et al. (1996). Characterization of a new melanocyte-specific gene (QNR-71) expressed in v-myc-transformed quail neuroretina. EMBO J 15: 3338–3350.

    Article  CAS  Google Scholar 

  • Wang GL, Timchenko NA . (2005). Dephosphorylated C/EBPα accelerates cell proliferation through sequestering retinoblastoma protein. Mol Cell Biol 25: 1325–1338.

    Article  CAS  Google Scholar 

  • Weterman MA, Ajubi N, van Dinter IM, Degen WG, van Muijen GN, Ruitter DJ et al. (1995). Nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts. Int J Cancer 60: 73–81.

    Article  CAS  Google Scholar 

  • Zhang XY, DeSalle LM, Patel JH, Capobianco AJ, Yu D, Thomas-Tikhonenko A et al. (2005). Metastasis-associated protein 1 (MTA1) is an essential downstream effector of the c-MYC oncoprotein. Proc Natl Acad Sci USA 102: 13968–13973.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Doris Bratschun for expert technical assistance. This work was supported by Austrian Science Foundation Grants P17041 (to KB) and P18148 (to MH).

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  1. Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria

    F Reiter, M Hartl, A I Karagiannidis & K Bister

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  1. F Reiter
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Correspondence to K Bister.

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Reiter, F., Hartl, M., Karagiannidis, A. et al. WS5, a direct target of oncogenic transcription factor Myc, is related to human melanoma glycoprotein genes and has oncogenic potential. Oncogene 26, 1769–1779 (2007). https://doi.org/10.1038/sj.onc.1209975

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