Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Oncogenomics
  • Published:

Overexpression of SERTAD3, a putative oncogene located within the 19q13 amplicon, induces E2F activity and promotes tumor growth

Oncogene volume 26, pages 4319–4328 (2007)Cite this article

Abstract

The amplified region of chromosome 19q13.1–13.2 has been associated with several cancers. The well-characterized oncogene AKT2 is located in this amplicon. Two members of the same gene family (SERTAD1 and SERTAD3) are also located within this region. We report herein the genomic structure and potential functions of SERTAD3. SERTAD3 has two transcript variants with short mRNA half-lives, and one of the variants is tightly regulated throughout G1 and S phases of the cell cycle. Overexpression of SERTAD3 induces cell transformation in vitro and tumor formation in mice, whereas inhibition of SERTAD3 by small interfering RNA (siRNA) results in a reduction in cell growth rate. Furthermore, luciferase assays based on E2F-1 binding indicate that SERTAD3 increases the activity of E2F, which is reduced by inhibition of SERTAD3 by siRNA. Together, our data support that SERTAD3 contributes to oncogenesis, at least in part, via an E2F-dependent mechanism.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Abdullah JM, Jing X, Spassov DS, Nachtman RG, Jurecic R . (2001). Cloning and characterization of Hepp, a novel gene expressed preferentially in hematopoietic progenitors and mature blood cells. Blood Cells Mol Dis 27: 667–676.

    Article  CAS  Google Scholar 

  • Alarcon-Vargas D, Ronai Z . (2004). c-Jun-NH2 kinase (JNK) contributes to the regulation of c-Myc protein stability. J Biol Chem 279: 5008–5016.

    Article  CAS  Google Scholar 

  • Alitalo K, Schwab M, Lin CC, Varmus HE, Bishop JM . (1983). Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc Natl Acad Sci USA 80: 1707–1711.

    Article  CAS  Google Scholar 

  • Barker PE . (1982). Double minutes in human tumor cells. Cytogenetics 5: 81–94.

    Article  CAS  Google Scholar 

  • Beghini A, Magnani I, Roversi G, Piepoli T, Di Terlizzi S, Moroni RF et al. (2003). The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines. Oncogene 22: 2581–2591.

    Article  CAS  Google Scholar 

  • Bicher A, Ault K, Kimmelman A, Gershenson D, Reed E, Liang B . (1997). Loss of heterozygosity in human ovarian cancer on chromosome 19q. Gynecol Oncol 66: 36–40.

    Article  CAS  Google Scholar 

  • Bienz M . (2006). The PHD finger, a nuclear protein-interaction domain. Trends Biochem Sci 31: 35–40.

    Article  CAS  Google Scholar 

  • Calgaro S, Boube M, Cribbs DL, Bourbon H-M . (2002). The Drosophila gene taranis encodes a novel trithorax group member potentially linked to the cell cycle regulatory apparatus. Genetics 160: 547–560.

    CAS  PubMed Central  Google Scholar 

  • Cho JM, Song DJ, Bergeron J, Benlimame N, Wold MS, Alaoui-Jamali MA . (2000). SERTAD3, a novel transcriptional co-activator, binds the second subunit of replication protein A. Nucleic Acids Res 28: 3478–3485.

    Article  CAS  Google Scholar 

  • Curtis LJ, Li Y, Gerbault-Seureau M, Kuick R, Dutrillaux AM, Goubin G . (1998). Amplification of DNA sequences from chromosome 19q13.1 in human pancreatic cell lines. Genomics 53: 42–55.

    Article  CAS  Google Scholar 

  • Gupta S, Takhar PP, Degenkolbe R, Koh CH, Zimmermann H, Yang CM . (2003). The human papillomavirus type 11 and 16 E6 proteins modulate the cell-cycle regulator and transcription cofactor TRIP-Br1. Virology 317: 155–164.

    Article  CAS  Google Scholar 

  • Hiemstra JL, Schneider SS, Brodeur GM . (1994). High-resolution mapping of the N-myc amplicon core domain in neuroblastomas. Prog Clin Biol Res 385: 51–57.

    CAS  Google Scholar 

  • Hoglund M, Gorunova L, Andren-Sandberg A, Dawiskiba S, Mitelman F, Johansson B . (1998). Cytogenetic and fluorescence in situ hybridization analyses of chromosome 19 aberrations in pancreatic carcinomas: frequent loss of 19p13.3 and gain of 19q131–13.2. Genes Chromosomes Cancer 21: 8–16.

    Article  CAS  Google Scholar 

  • Hsu SI, Yang CM, Sim KG, Hentschel DM, O'Leary E, Bonventre JV . (2001). TRIP-Br: a novel family of PHD zinc finger- and bromodomain-interacting proteins that regulate the transcriptional activity of E2F-1/DP-1. EMBO J 20: 2273–2285.

    Article  CAS  Google Scholar 

  • Lengauer C, Kinzler KW, Vogelstein B . (1998). Genetic instabilities in human cancers. Nature 396: 643–649.

    Article  CAS  Google Scholar 

  • Loignon M, Drobetsky EA . (2002). The initiation of UV-induced G(1) arrest in human cells is independent of the p53/p21/pRb pathway but can be attenuated through expression of the HPV E7 oncoprotein. Carcinogenesis 23: 35–45.

    Article  CAS  Google Scholar 

  • Luoh SW . (2002). Amplification and expression of genes from the 17q11 approximately q12 amplicon in breast cancer cells. Cancer Genet Cytogenet 136: 43–47.

    Article  CAS  Google Scholar 

  • Marchio A, Meddeb M, Pineau P, Danglot G, Tiollais P, Bernheim A et al. (1997). Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer 18: 59–65.

    Article  CAS  Google Scholar 

  • Miwa W, Yasuda J, Murakami Y, Yashima K, Sugano K, Sekine T et al. (1996). Isolation of DNA sequences amplified at chromosome 19q13.1–q13.2 including the AKT2 locus in human pancreatic cancer. Biochem Biophys Res Commun 225: 968–974.

    Article  CAS  Google Scholar 

  • Morgenstern JP, Land H . (1990). Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res 18: 3587–3596.

    Article  CAS  Google Scholar 

  • Muleris M, Almeida A, Gerbault-Seureau M, Malfoy B, Dutrillaux B . (1995). Identification of amplified DNA sequences in breast cancer and their organization within homogeneously staining regions. Genes Chromosomes Cancer 14: 155–163.

    Article  CAS  Google Scholar 

  • Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B . (1992). Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358: 80–83.

    Article  CAS  Google Scholar 

  • Ormandy CJ, Musgrove EA, Hui R, Daly RJ, Sutherland RL . (2003). Cyclin D1, EMS1 and 11q13 amplification in breast cancer. Breast Cancer Res Treat 78: 323–335.

    Article  CAS  Google Scholar 

  • Petersen I, Langreck H, Wolf G, Schwendel A, Psille R, Vogt P et al. (1997). Small-cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p. Br J Cancer 75: 79–86.

    Article  CAS  Google Scholar 

  • Reifenberger G, Liu L, Ichimura K, Schmidt EE, Collins VP . (1993). Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res 53: 2736–2739.

    CAS  Google Scholar 

  • Ross JS, Fletcher JA . (1999). The HER-2/neu oncogene: prognostic factor, predictive factor, and target for therapy. Semin Cancer Biol 9: 125–138.

    Article  CAS  Google Scholar 

  • Schneider SS, Hiemstra JL, Zehnbauer BA, Taillon-Miller P, Le Paslier DL, Vogelstein B et al. (1992). Isolation and structural analysis of a 12-megabase N-myc amplicon from a human neuroblastoma. Mol Cell Biol 12: 5563–5570.

    Article  CAS  Google Scholar 

  • Shiloh Y, Korf B, Kohl NE, Sakai K, Brodeur GM, Harris P et al. (1986). Amplification and rearrangement of DNA sequences from the chromosomal region 2p24 in human neuroblastomas. Cancer Res 46: 5297–5301.

    CAS  Google Scholar 

  • Sieber OM, Heinimann K, Tomlinson IP . (2003). Genomic instability – the engine of tumorigenesis? Nat Rev Cancer 3: 701–708.

    Article  CAS  Google Scholar 

  • Singh P, Wong SH, Hong W . (1994). Overexpression of E2F-1 in rat embryo fibroblasts leads to neoplastic transformation. EMBO J 13: 3329–3338.

    Article  CAS  Google Scholar 

  • Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A et al. (1999). Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1). Genes Dev 13: 3027–3033.

    Article  CAS  Google Scholar 

  • Tang TC, Sham JS, Xie D, Fang Y, Huo KK, Wu QL et al. (2002). Identification of a candidate oncogene SEI-1 within a minimally amplified region at 19q13.1 in ovarian cancer cell lines. Cancer Res 62: 7157–7161.

    CAS  Google Scholar 

  • Thompson FH, Nelson MA, Trent JM, Guan XY, Liu Y, Yang JM et al. (1996). Amplification of 19q13.1–q13.2 sequences in ovarian cancer. G-band, FISH, and molecular studies. Cancer Genet Cytogenet 87: 55–62.

    Article  CAS  Google Scholar 

  • Wang ZJ, Churchman M, Campbell IG, Xu WH, Yan ZY, McCluggage WG et al. (1999). Allele loss and mutation screen at the Peutz–Jeghers (LKB1) locus (19p13.3) in sporadic ovarian tumors. Br J Cancer 80: 70–72.

    Article  CAS  Google Scholar 

  • Yang XH, Sladek TL . (1995). Overexpression of the E2F-1 transcription factor gene mediates cell transformation. Gene Exp 4: 195–204.

    CAS  Google Scholar 

  • Yen L, Benlimame N, Nie Z, Xiao D, Wang T, Al Moustafa A et al. (2002). Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. Mol Biol Cell 13: 4029–4044.

    Article  CAS  Google Scholar 

  • Zaharieva BM, Simon R, Diener PA, Ackermann D, Maurer R, Alund G et al. (2003). High-throughput tissue microarray analysis of 11q13 gene amplification (CCND1, FGF3, FGF4, EMS1) in urinary bladder cancer. J Pathol 201: 603–608.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Masataka Sugimoto (Paterson Institute for Cancer Research) for donating a FLAG-tagged SERTAD1 expression vector and Dr Marie Classon (Massachusetts General Hospital Cancer Center, USA) for donating the E2F luciferase reporter plasmid (pLuc-(E2F)4) and the E2F-1 expression vector. This work was supported by the Canadian Breast Cancer Research Alliance and in part by the Canadian Institutes for Health Research. M Alaoui-Jamali is an FRSQ Scholar and Dundi and Lyon Sachs Distinguished Scientist. H Darwish was supported by NSERC.

Author information

Authors and Affiliations

  1. Departments of Medicine and Oncology, Faculty of Medicine, Lady Davis Institute for Medical Research and Segal Comprehensive Cancer Center of the Sir Mortimer B Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada

    H Darwish, J M Cho, M Loignon & M A Alaoui-Jamali

Authors
  1. H Darwish
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Loignon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M A Alaoui-Jamali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M A Alaoui-Jamali.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Darwish, H., Cho, J., Loignon, M. et al. Overexpression of SERTAD3, a putative oncogene located within the 19q13 amplicon, induces E2F activity and promotes tumor growth. Oncogene 26, 4319–4328 (2007). https://doi.org/10.1038/sj.onc.1210195

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210195

Keywords

This article is cited by

Search

Advanced search

Quick links