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:

Co-resistance to retinoic acid and TRAIL by insertion mutagenesis into RAM

Oncogene volume 25, pages 3735–3744 (2006)Cite this article

Abstract

Retinoic acid (RA), used as first-line therapy for acute promyelocytic leukemia (APL), exerts its antileukemic activity by inducing blast differentiation and activating tumor-selective TNF-related apoptosis-inducing ligand (TRAIL) signaling. To identify downstream mediators of RA signaling, we used retrovirus-mediated insertion mutagenesis in PLB985 leukemia cells and established the RA-resistant cell line WY-1. In PLB985, but not WY-1 cells, RA induced TRAIL and its DR4 and DR5 receptors. Knocking down TRAIL expression by RNA interference blocked RA-induced apoptosis. WY-1 cells are defective for RA-induced differentiation, G1 arrest and exhibit co-resistance to TRAIL. In WY-1 cells, a single virus copy is integrated into a novel RA-regulated gene termed RAM (retinoic acid modulator). RAM is expressed in the myelomonocytic lineage and extinguished by RA in PLB985, but not WY-1 cells. Whereas knocking down RAM expression by RNA interference promoted RA-induced differentiation and TRAIL-triggered apoptosis of PLB985 and WY-1 cells, overexpression of the predicted 109 amino-acid RAM open reading frame did not alter RA signaling in PLB985 cells. This indicates that, apart from encoding the putative RAM protein, RAM RNA may exert additional functions that are impaired by the retrovirus insertion. Our study demonstrates that RA induction of the TRAIL pathway is also operative in leukemia cells lacking an RARα oncofusion protein and identifies RAM as a novel RA-dependent modulator of myeloid differentiation and death.

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
Figure 7

Similar content being viewed by others

References

  • Altucci L, Gronemeyer H . (2001). Nat Rev Cancer 1: 181–193.

  • Altucci L, Gronemeyer H . (2004). In: Litwack G (ed). Vitamins and Hormones, vol. 67. Academic Press, Elsevier: Amsterdam. pp 319–345.

    Google Scholar 

  • Altucci L, Rossin A, Hirsch O, Nebbioso A, Vitoux D, Wilhelm D et al. (2005). Cancer Res 65: 8754–8765.

  • Altucci L, Rossin A, Raffelsberger W, Reitmair A, Chomienne C, Gronemeyer H . (2001). Nat Med 7: 680–686.

  • Baetu TM, Kwon H, Sharma S, Grandvaux N, Hiscott J . (2001). J Immunol 167: 3164–3173.

  • Bernard D, Quatannens B, Vandenbunder B, Abbadie C . (2001). J Biol Chem 276: 27322–27328.

  • Chen JY, Clifford J, Zusi C, Starrett J, Tortolani D, Ostrowski J et al. (1996). Nature 382: 819–822.

  • Clagett-Dame M, DeLuca HF . (2002). Annu Rev Nutr 22: 347–381.

  • Clarke N, Jimenez-Lara AM, Voltz E, Gronemeyer H . (2004). EMBO J 23: 3051–3060.

  • Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ . (2002). J Immunol 168: 1356–1361.

  • de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A . (1991). Cell 66: 675–684.

  • Drexler HG, Dirks WG, Matsuo Y, MacLeod RA . (2003). Leukemia 17: 416–426.

  • Gavalas A . (2002). Trends Neurosci 25: 61–64.

  • Gronemeyer H, Gustafsson JA, Laudet V . (2004). Nat Rev Drug Design 3: 950–964.

  • Hansen LA, Sigman CC, Andreola F, Ross SA, Kelloff GJ, De Luca LM . (2000). Carcinogenesis 21: 1271–1279.

  • Hong WK, Sporn MB . (1997). Science 278: 1073–1077.

  • Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F, Viale A et al. (2005). Nat Med 11: 71–76.

  • Kakizuka A, Miller Jr WH, Umesono K, Warrell Jr RP, Frankel SR, Murty VV et al. (1991). Cell 66: 663–674.

  • Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A . (2000). Immunity 12: 611–620.

  • Laudet V, Gronemeyer H . (2002). The Nuclear Receptor Facts Book. Academic Press: San Diego, San Francisco, NY.

    Google Scholar 

  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES et al. (1997). Cell 91: 479–489.

  • Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . (1998). Cell 94: 481–490.

  • MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES . (1997). J Biol Chem 272: 25417–25420.

  • Mader S, Chen JY, Chen Z, White J, Chambon P, Gronemeyer H . (1993). EMBO J 12: 5029–5041.

  • Miller AD, Rosman GJ . (1989). Biotechniques 7: 980–982, 984–986, 989–990.

  • Monczak Y, Trudel M, Lamph WW, Miller Jr WH . (1997). Blood 90: 3345–3355.

  • Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM . (1998). J Biol Chem 273: 2926–2930.

  • Nagy L, Thomazy VA, Shipley GL, Fesus L, Lamph W, Heyman RA et al. (1995). Mol Cell Biol 15: 3540–3551.

  • Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P et al. (2005). Nat Med 11: 77–84.

  • Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J et al. (1997). Science 276: 111–113.

  • Pandolfi PP, Grignani F, Alcalay M, Mencarelli A, Biondi A, LoCoco F et al. (1991). Oncogene 6: 1285–1292.

  • Ravi R, Bedi GC, Engstrom LW, Zeng Q, Mookerjee B, Gelinas C et al. (2001). Nat Cell Biol 3: 409–416.

  • Salvesen GS, Dixit VM . (1999). Proc Natl Acad Sci USA 96: 10964–10967.

  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ et al. (1998). EMBO J 17: 1675–1687.

  • Secchiero P, Milani D, Gonelli A, Melloni E, Campioni D, Gibellini D et al. (2003). J Leukoc Biol 74: 223–232.

  • Sedger LM, Glaccum MB, Schuh JC, Kanaly ST, Williamson E, Kayagaki N et al. (2002). Eur J Immunol 32: 2246–2254.

  • Shiozaki EN, Chai J, Shi Y . (2002). Proc Natl Acad Sci USA 99: 4197–4202.

  • Sprick MR, Rieser E, Stahl H, Grosse-Wilde A, Weigand MA, Walczak H . (2002). EMBO J 21: 4520–4530.

  • Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES . (1998). Mol Cell 1: 949–957.

  • Suliman A, Lam A, Datta R, Srivastava RK . (2001). Oncogene 20: 2122–2133.

  • Sun SY, Lotan R . (2002). Crit Rev Oncol Hematol 41: 41–55.

  • Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S et al. (2001). Nat Med 7: 94–100.

  • Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Kayagaki N, Yagita H et al. (2002). J Exp Med 195: 161–169.

  • Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, Tanner JE et al. (2004). J Exp Med 199: 437–448.

  • Tucker KA, Lilly MB, Heck Jr L, Rado TA . (1987). Blood 70: 372–378.

  • Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N et al. (1997). EMBO J 16: 5386–5397.

  • Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ . (1996). Genes Dev 10: 2859–2869.

  • Watabe K, Ito A, Asada H, Endo Y, Kobayashi T, Nakamoto K et al. (2001). Jpn J Cancer Res 92: 140–151.

  • Yin W, Raffelsberger W, Gronemeyer H . (2005). Int J Biochem Cell Biol 37: 1696–1708.

  • Zou H, Henzel WJ, Liu X, Lutschg A, Wang X . (1997). Cell 90: 405–413.

  • Zou H, Li Y, Liu X, Wang X . (1999). J Biol Chem 274: 11549–11556.

Download references

Acknowledgements

We thank Lucia Altucci for inspiring this work and critical discussions, Ana Jimenez-Lara for TRAIL siRNA, Fengjun Li and Michèle Lieb for technical assistance, Jean-Marie Garnier for the pSG5-RAM/B10 and pLenti6-RAM/V5 construction, Michel Koenig (IGBMC) for PLB985 and WY-1 genotyping, M Lazar (University of Pennsylvania, Philadelphia) for pLXSN, PG Pelicci (IEO, Milano) for the PA317 packaging cell-line, Yvon Cayre (Paris) for PLB985 cells, and Chris Zusi and Marco Gottardis (Bristol–Myers Squibb) for synthetic retinoids. This work was supported by funds from the Association for International Cancer Research (AICR grants 00-108 and 05-130), the European Community (HPRN-CT2002-00268, QLK3-CT2002-O2029, LSHC-CT2005-518417), the Hôpital Universitaire de Strasbourg (HUS), the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Centre National de la Recherche Scientifique (CNRS).

Author information

Author notes

  1. W Yin & J L Clifford

    Present address: Department of Biochemistry and Molecular Biology, LSUHSC, 1501 Kings Highway, PO Box 33932, Shreveport, LA, 71130-3932, USA

Authors and Affiliations

  1. Department of Cell Biology and Signal Transduction, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, Illkirch Cedex, C U de Strasbourg, France

    W Yin, A Rossin, J L Clifford & H Gronemeyer

Authors
  1. W Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Rossin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J L Clifford
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Gronemeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Gronemeyer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yin, W., Rossin, A., Clifford, J. et al. Co-resistance to retinoic acid and TRAIL by insertion mutagenesis into RAM. Oncogene 25, 3735–3744 (2006). https://doi.org/10.1038/sj.onc.1209410

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209410

Keywords

This article is cited by

Search

Advanced search

Quick links