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N-MYC promotes cell proliferation through a direct transactivation of neuronal leucine-rich repeat protein-1 (NLRR1) gene in neuroblastoma

Oncogene volume 27, pages 6075–6082 (2008)Cite this article

Abstract

Neuronal leucine-rich repeat protein-1 (NLRR1) gene encodes a type I transmembrane protein with unknown function. We have previously described that NLRR1 gene is highly expressed in unfavorable neuroblastomas as compared with favorable tumors and its higher expression levels correlate significantly with poor clinical outcome. In this study, we have found that NLRR1 gene is one of direct target genes for N-MYC and its gene product contributes to N-MYC-dependent growth promotion in neuroblastoma. Expression levels of NLRR1 were significantly associated with those of N-MYC in various neuroblastoma cell lines as well as primary neuroblastoma tissues. Indeed, enforced expression of N-MYC resulted in a remarkable induction of the endogenous NLRR1. Consistent with these results, we have identified two functional E-boxes within the promoter region and intron 1 of NLRR1 gene. Intriguingly, c-myc also transactivated NLRR1 gene. Enforced expression of NLRR1 promoted cell proliferation and rendered cells resistant to serum deprivation. In support with these observations, small-interfering RNA-mediated knockdown of the endogenous NLRR1-reduced growth rate and sensitized cells to serum starvation. Collectively, our present findings provide a novel insight into understanding molecular mechanisms behind aggressive neuroblastoma with N-MYC amplification.

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References

  • Alex R, Sozeri O, Meyer S, Dildrop R . (1992). Determination of the DNA sequence recognized by the bHLH-zip domain of the N-Myc protein. Nucleic Acids Res 20: 2257–2263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bando T, Sekine K, Kobayashi S, Watabe AM, Rump A, Tanaka M et al. (2005). Neuronal leucine-rich repeat protein 4 functions in hippocampus-dependent long-lasting memory. Mol Cell Biol 25: 4166–4175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernards R, Dessain SK, Weinberg RA . (1986). N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma. Cell 47: 667–674.

    Article  CAS  PubMed  Google Scholar 

  • Blackwood EM, Eisenman RN . (1991). Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA binding complex with Myc. Science 251: 1211–1217.

    Article  CAS  PubMed  Google Scholar 

  • Blackwood EM, Kretzner I, Eisenman RN . (1992). Myc and Max function as a nucleoprotein complex. Curr Opin Genet Dev 2: 227–235.

    Article  CAS  PubMed  Google Scholar 

  • Boon K, Caron HN, van Asperen R, Valentijn L, Hermus MC, van Sluis P et al. (2001). N-myc enhances the expression of a large set of genes functioning ribosome biogenesis and protein synthesis. EMBO J 20: 1383–1393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brodeur GM, Nakagawara A . (1992). Molecular basis of clinical heterogeneity in neuroblastoma. Am J Pediatr Hematol Oncol 14: 111–116.

    Article  CAS  PubMed  Google Scholar 

  • Degterev A, Boyce M, Yuan J . (2003). A decade of caspases. Oncogene 22: 8543–8567.

    Article  CAS  PubMed  Google Scholar 

  • Fukamachi K, Matsuoka Y, Ohno H, Hamaguchi T, Tsuda H . (2002). Neuronal leucine-rich repeat protein-3 amplifies MAPK activation by epidermal growth factor through a carboxyl-terminal region containing endocytosis motifs. J Biol Chem 277: 43549–43552.

    Article  CAS  PubMed  Google Scholar 

  • Hamano S, Ohira M, Isogai E, Nakada K, Nakagawara A . (2004). Identification of novel human neuronal leucine-rich repeat (hNLRR) family, genes and inverse association of expression of Nbla10449/hNLRR-1 and Nbla10677/hNLRR-3 with the prognosis of primary neuroblastomas. Int J Oncol 24: 1457–1466.

    CAS  PubMed  Google Scholar 

  • Kohl NE, Kanda N, Schreck RR, Bruns G, Latt SA, Gilbert F et al. (1983). Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell 35: 359–367.

    Article  CAS  PubMed  Google Scholar 

  • Kouzarides T, Ziff E . (1988). The role of the leucine zipper in the fos-jun interaction. Nature 336: 646–651.

    Article  CAS  PubMed  Google Scholar 

  • Landschulz WH, Johnson PF, McKnight S . (1988). The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science 240: 1759–1764.

    Article  CAS  PubMed  Google Scholar 

  • Lasorella A, Noseda M, Beyna M, Iavarone A . (2000). Id2 is a retinoblastoma protein target and mediates signaling by Myc oncoproteins. Nature 407: 592–598.

    Article  CAS  PubMed  Google Scholar 

  • Lutz W, Stohr M, Schurmann J, Wenzel A, Lohr A, Schwab M . (1996). Conditional expression of N-myc in human neuroblastoma cells increases expression of a-prothymosin and ornithine decarboxylase and accelerates progression into S-phase early after mitogenic stimulation of quiescent cells. Oncogene 13: 803–812.

    CAS  PubMed  Google Scholar 

  • Murre C, Schonleber McCaw P, Baltimore D . (1989). A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56: 777–783.

    Article  CAS  PubMed  Google Scholar 

  • Negroni A, Scarpa S, Romeo A, Ferrari S, Modesti A, Raschella G . (1991). Decrease of proliferation rate and induction of differentiation by a MYCN antisense DNA oligomer in a human neuroblastoma cell line. Cell Growth Differ 2: 511–518.

    CAS  PubMed  Google Scholar 

  • Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM, Gilbert F et al. (1983). Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature 305: 245–248.

    Article  CAS  PubMed  Google Scholar 

  • Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY et al. (1985). Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 313: 1111–1116.

    Article  CAS  PubMed  Google Scholar 

  • Slack A, Chen Z, Tonelli R, Pule M, Hunt L, Pession A et al. (2005). The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proc Natl Acad Sci USA 102: 731–736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taguchi A, Wanaka A, Mori T, Matsumoto K, Imai Y, Takagi T et al. (1996). Molecular cloning of novel leucine-rich repeat proteins and their expression in the developing mouse nervous system. Brain Res Mol Brain Res 35: 31–40.

    Article  CAS  PubMed  Google Scholar 

  • Taniguchi H, Tohyama A, Takagi T . (1996). Cloning and expression of a novel gene for a protein with leucine-rich repeats in the developing mouse nervous system. Brain Res Mol Brain Res 36: 45–52.

    Article  CAS  PubMed  Google Scholar 

  • Torres R, Schreiber-Agus N, Morgenbesser SD, DePinho RA . (1992). Myc and Max: a putative transcriptional complex in search of a cellular target. Curr Opin Cell Biol 4: 468–474.

    Article  CAS  PubMed  Google Scholar 

  • Truscott M, Denault JB, Goulet B, Leduy L, Salvesen GS, Nepveu A . (2007). Carboxy-terminal proteolytic processing of CUX1 by a caspase enables transcriptional activation in proliferating cells. J Biol Chem 282: 30216–30226.

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Xie I, Allan S, Beach D, Hannon G . (1998). Myc activates telomerase. Genes Dev 12: 1769–1774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM . (1997). Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J 16: 2985–2995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to Dr M Schwab for providing the expression plasmid for N-MYC. We thank Ms Y Nakamura for technical assistance. This work was supported in part by a Grant-in-Aid from the Ministry of Health, Labour and Welfare for Third Term Comprehensive Control Research for Cancer, a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan, a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, Uehara Memorial Foundation and Hisamitsu Pharmaceutical Co.

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Author notes

  1. M S Hossain, T Ozaki and H Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba, Japan

    M S Hossain, T Ozaki, H Wang, H Takenobu, M Ohira, T Kamijo & A Nakagawara

  2. Department of Molecular Biology and Oncology, Chiba University Graduate School of Medicine, Chiba, Japan

    M S Hossain, T Ozaki & A Nakagawara

  3. Department of Pediatrics, ShengJing Hospital of China Medical University, Shenyang, People's Republic of China

    H Wang

  4. Department of Pathology, National Center for Child Health and Development, Tokyo, Japan

    A Nakagawa

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  1. M S Hossain
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  2. T Ozaki
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  3. H Wang
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  4. A Nakagawa
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  6. M Ohira
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  7. T Kamijo
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  8. A Nakagawara
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Correspondence to A Nakagawara.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Hossain, M., Ozaki, T., Wang, H. et al. N-MYC promotes cell proliferation through a direct transactivation of neuronal leucine-rich repeat protein-1 (NLRR1) gene in neuroblastoma. Oncogene 27, 6075–6082 (2008). https://doi.org/10.1038/onc.2008.200

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