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.

  • Original Article
  • Published:

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

Oncogene volume 25, pages 6252–6261 (2006)Cite this article

Abstract

The IG20 gene is overexpressed in human tumors and cancer cell lines, and encodes at least four splice variants (SVs) namely, IG20pa, MADD, IG20-SV2 and DENN-SV. Earlier, gain-of-function studies showed that IG20-SVs can exhibit diverse functions and play a critical role in cell proliferation and apoptosis. Expression of exogenous IG20pa or DENN-SV rendered cells either susceptible or resistant to induced apoptosis, respectively, whereas MADD and IG20-SV2 had no apparent effect. In order to understand the contrasting effects of the IG20-SVs in a physiologically more relevant system, we expressed exon-specific small hairpin RNAs (shRNAs) to selectively knockdown specific IG20-SVs. Consistent with an earlier study, knockdown of all IG20-SVs resulted in spontaneous apoptosis of HeLa and PA-1 cells. In addition, we unambiguously demonstrated that knockdown of MADD can render cells susceptible to spontaneous apoptosis but had no discernible effect on cell proliferation, colony size or cell cycle progression. Moreover, expression of MADD alone, and not DENN-SV, in the absence of endogenous IG20-SVs was sufficient to prevent spontaneous apoptosis. Our results show the utility of shRNAs for selective knockdown of particular IG20-SVs and their potential therapeutic value in cancer. Further, they demonstrate that MADD alone is sufficient and necessary for cancer cell survival.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • 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
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Al-Zoubi AM, Efimova EV, Kaithamana S, Martinez O, El-Idrissi ME, Dogan RE et al. (2001). J Biol Chem 276: 47202–47211.

  • Andreadis A, Gallego ME, Nadal-Ginard B . (1987). Annu Rev Cell Biol 3: 207–242.

  • Brinkman BM, Telliez JB, Schievella AR, Lin LL, Goldfeld AE . (1999). J Biol Chem 274: 30882–30886.

  • Brown TL, Howe PH . (1998). Curr Biol 8: R191.

  • Brummelkamp TR, Bernards R, Agami R . (2002). Science 296: 550–553.

  • Chow VT, Lee SS . (1996). DNA Seq 6: 263–273.

  • Chow VT, Lim KM, Lim D . (1998). Genome 41: 543–552.

  • Cullen BR . (2004). Virus Res 102: 3–9.

  • Cullen BR . (2005). Gene Therapy 6: 503–508.

  • Cunningham SJ . (1996). Cloning and characterization of a novel cDNA isolated from human beta cells.PhD thesis. The University of Texas Medical Branch, Galveston, TX.

    Google Scholar 

  • Del Villar K, Miller CA . (2004). Proc Natl Acad Sci USA 101: 4210–4215.

  • Efimova EV, Al-Zoubi AM, Martinez O, Kaithamana S, Lu SF, Arima T et al. (2004). Oncogene 23: 1076–1087.

  • Efimova EV, Martinez O, Lokshin A, Arima T, Prabhakar BS . (2003). Cancer Res 63: 8768–8776.

  • Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T . (2001a). Nature 411: 494–498.

  • Elbashir SM, Lendeckel W, Tuschl T . (2001b). Genes Dev 15: 188–200.

  • Goto Y, De Silva MG, Toscani A, Prabhakar BS, Notkins AL, Lan MS . (1992). J Biol Chem 267: 15252–15257.

  • Hall J . (2004). Nat Rev Genet 5: 552–557.

  • Hutvágner G, Zamore PD . (2002). Science 297: 2056–2060.

  • Iwasaki K, Toyonaga R . (2000). EMBO J 19: 4806–4816.

  • Johnstone RW, Ruefli AA, Lowe SW . (2002). Cell 108: 153–164.

  • Kerr JF, Wyllie AH, Currie AR . (1972). Br J Cancer 26: 239–257.

  • Lee MT, Coburn GA, McClure MO, Cullen BR . (2003). J Virol 77: 11964–11972.

  • Levivier E, Goud B, Souchet M, Calmels TP, Mornon JP, Callebaut I . (2001). Biochem Biophys Res Commun 287: 688–695.

  • Lim KM, Chow VT . (2002). Mol Carcinog 35: 110–126.

  • Lim KM, Yeo WS, Chow VT . (2004). Int J Cancer 109: 24–37.

  • McManus MT, Sharp PA . (2002). Nat Rev Genet 3: 737–747.

  • Murakami-Mori K, Mori S, Bonavida B, Nakamura S . (1999). J Immunol 162: 3672–3679.

  • Ramaswamy M, Efimova EV, Martinez O, Mulherkar NU, Singh SP, Prabhakar BS . (2004). Oncogene 23: 6083–6094.

  • Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A . (2004). Nat Biotechnol 22: 326–330.

  • Schievella AR, Chen JH, Graham JR, Lin LL . (1997). J Biol Chem 272: 12069–12075.

  • Tanaka M, Miyoshi J, Ishizaki H, Togawa A, Ohnishi K, Endo K et al. (2001). Mol Biol Cell 12: 1421–1430.

  • Telliez JB, Bean KM, Lin LL . (2000). Biochem Biophys Acta 1478: 280–288.

  • Wada M, Nakanishi H, Satoh A, Hirano H, Obaishi H, Matsuura Y et al. (1997). J Biol Chem 272: 3875–3878.

  • Yamaguchi K, Tanaka M, Mizoguchi A, Hirata Y, Ishizaki H, Kaneko K et al. (2002). Proc Natl Acad Sci USA 99: 14536–14541.

  • Zhang Y, Zhou L, Miller CA . (1998). Proc Natl Acad Sci USA 95: 2586–2591.

Download references

Acknowledgements

We thank Dr Reuven Agami for pSUPER, Dr BR Cullen and Dr TJ Hope for lentivirus system, Dr Chenthamarakshan Vasu for help with CFSE staining, Dr Balaji Manicassamy for help with mutant-construct generation and Dr Prasad Kanteti for his valuable critique. This work was in part supported by grant #5R01CA107506 from National Institutes of Health, Bethesda, MD.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    N Mulherkar, D C Mordi & B S Prabhakar

  2. National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    M Ramaswamy

Authors
  1. N Mulherkar
    View author publications

    Search author on:PubMed Google Scholar

  2. M Ramaswamy
    View author publications

    Search author on:PubMed Google Scholar

  3. D C Mordi
    View author publications

    Search author on:PubMed Google Scholar

  4. B S Prabhakar
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to B S Prabhakar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mulherkar, N., Ramaswamy, M., Mordi, D. et al. MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival. Oncogene 25, 6252–6261 (2006). https://doi.org/10.1038/sj.onc.1209650

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.onc.1209650

Keywords

This article is cited by

Search

Advanced search

Quick links