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A moderate reduction of Bcl-xL expression protects against tumorigenesis; however, it also increases susceptibility to tissue injury


Little consideration has been given to the possibility that there could be variations in protein expression that alter susceptibility to tumorigenesis without causing other obvious phenotypic effects. Therefore, we sought to determine if haploinsufficiency for the antiapoptotic protein Bcl-xL would affect tumorigenesis. We chose to study Bcl-xL because although bcl-x+/– mice were thought to be phenotypically normal, we and others found that haploinsufficiency for Bcl-xL lowers fibroblast resistance to apoptosis in tissue culture. Since resistance to certain forms of apoptosis is required for tumor formation, this suggested that decreased Bcl-xL expression would afford protection against tumorigenesis. Indeed, we demonstrate here that bcl-x+/– mice are strikingly resistant to carcinogen-induced tumorigenesis. However, we found that they pay a price for their resistance in that they are more susceptible to clinically relevant forms of tissue injury – they suffer increased hepatic injury in a model of binge alcohol abuse and in response to TNF-α treatment. These findings are important because they suggest that even minor variations in Bcl-xL expression could affect susceptibility to cancer and other diseases. Additionally, they indicate that the potential for increased susceptibility to tissue injury must be considered in the design of chemopreventative and antineoplastic strategies that involve inhibition of Bcl-xL activity.

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  • Amundson SA, Myers TG, Scudiero D, Kitada S, Reed JC and Fornace Jr AJ . (2000). Cancer Res., 60, 6101–6110.

  • Becker U, Deis A, Sorensen TI, Gronbaek M, Borch-Johnsen K, Muller CF, Schnohr P and Jensen G . (1996). Hepatology, 23, 1025–1029.

  • Bergsland EK . (2001). Semin. Oncol., 28, 521–531.

  • Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G and Thompson CB . (1993). Cell, 74, 597–608.

  • Bradham CA, Plumpe J, Manns MP, Brenner DA and Trautwein C . (1998). Am. J. Physiol., 275, G387–G392.

  • Chen C, Edelstein LC and Gelinas C . (2000). Mol. Cell. Biol., 20, 2687–2695.

  • Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH and Ballard DW . (1997). Proc. Natl. Acad. Sci. USA, 94, 10057–10062.

  • Colantoni A, Idilman R, De Maria N, La Paglia N, Belmonte J, Wezeman F, Emanuele N, Van Thiel DH, Kovacs EJ and Emanuele MA . (2003). Alcohol Clin. Exp. Res., 27, 1184–1189.

  • Cossentino MJ and Wong RK . (2003). Semin. Gastrointest. Dis., 14, 128–135.

  • Day CP . (2001). J. Hepatol., 34, 330–333.

  • de la Coste A, Fabre M, McDonell N, Porteu A, Gilgenkrantz H, Perret C, Kahn A and Mignon A . (1999). Am. J. Physiol., 277, G702–G708.

  • Deverman BE, Cook BL, Manson SR, Niederhoff RA, Langer EM, Rosova I, Kulans LA, Fu X, Weinberg JS, Heinecke JW, Roth KA and Weintraub SJ . (2002). Cell, 111, 51–62.

  • Diehl AM . (2000). Immunol. Rev., 174, 160–171.

  • Dvorakova K, Payne CM, Ramsey L, Holubec H, Sampliner R, Dominguez J, Dvorak B, Bernstein H, Bernstein C, Prasad A, Fass R, Cui H and Garewal H . (2004). Clin. Cancer Res., 10, 2020–2028.

  • Gonzalez-Amaro R, Garcia-Monzon C, Garcia-Buey L, Moreno-Otero R, Alonso JL, Yague E, Pivel JP, Lopez-Cabrera M, Fernandez-Ruiz E and Sanchez-Madrid F . (1994). J. Exp. Med., 179, 841–848.

  • Green DR and Evan GI . (2002). Cancer Cell, 1, 19–30.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Hatano E and Brenner DA . (2001). Am. J. Physiol. Gastrointest. Liver Physiol., 281, G1357–G1368.

  • Hong F, Kim WH, Tian Z, Jaruga B, Ishac E, Shen X and Gao B . (2002). Oncogene, 21, 32–43.

  • Karnauskas R, Niu Q, Talapatra S, Plas DR, Greene ME, Crispino JD and Rudin CM . (2003). Oncogene, 22, 688–698.

  • Leist M, Gantner F, Bohlinger I, Germann PG, Tiegs G and Wendel A . (1994). J. Immunol., 153, 1778–1788.

  • Maclean KH, Keller UB, Rodriguez-Galindo C, Nilsson JA and Cleveland JL . (2003). Mol. Cell. Biol., 23, 7256–7270.

  • McManus DT, Olaru A and Meltzer SJ . (2004). Cancer Res., 64, 1561–1569.

  • Muto Y, Nouri-Aria KT, Meager A, Alexander GJ, Eddleston AL and Williams R . (1988). Lancet, 2, 72–74.

  • Naik P, Karrim J and Hanahan D . (1996). Genes Dev., 10, 2105–2116.

  • Natori S, Rust C, Stadheim LM, Srinivasan A, Burgart LJ and Gores GJ . (2001). J. Hepatol., 34, 248–253.

  • Ravi R, Bedi GC, Engstrom LW, Zeng Q, Mookerjee B, Gelinas C, Fuchs EJ and Bedi A . (2001). Nat. Cell Biol., 3, 409–416.

  • Riegman PH, Vissers KJ, Alers JC, Geelen E, Hop WC, Tilanus HW and van Dekken H . (2001). Cancer Res., 61, 3164–3170.

  • Sato N, Lindros KO, Baraona E, Ikejima K, Mezey E, Jarvelainen HA and Ramchandani VA . (2001). Alcohol Clin. Exp. Res., 25, 40S–45S.

  • Shimkin MB and Stoner GD . (1975). Adv. Cancer Res., 21, 1–58.

  • Taylor JK, Zhang QQ, Wyatt JR and Dean NM . (1999). Nat. Biotechnol., 17, 1097–1100.

  • Tzung SP, Fausto N and Hockenbery DM . (1997). Am. J. Pathol., 150, 1985–1995.

  • Van Antwerp DJ, Martin SJ, Verma IM and Green DR . (1998). Trends Cell Biol., 8, 107–111.

  • Wang CY, Guttridge DC, Mayo MW and Baldwin Jr AS . (1999). Mol. Cell. Biol., 19, 5923–5929.

  • Wang CY, Mayo MW, Korneluk RG, Goeddel DV and Baldwin Jr AS . (1998). Science, 281, 1680–1683.

  • Wetscher GJ, Schwelberger H, Unger A, Offner FA, Profanter C, Glaser K, Klingler A, Gadenstaetter M and Klinger P . (1998). Am. J. Surg., 176, 569–573.

  • Yoon JH and Gores GJ . (2002). J. Hepatol., 37, 400–410.

  • Zhang H, Taylor J, Luther D, Johnston J, Murray S, Wyatt JR, Watt AT, Koo S, York-DeFalco C, Stecker K and Dean NM . (2003). J. Pharmacol. Exp. Ther., 307, 24–33.

  • Ziol M, Tepper M, Lohez M, Arcangeli G, Ganne N, Christidis C, Trinchet JC, Beaugrand M, Guillet JG and Guettier C . (2001). J. Hepatol., 34, 254–260.

  • Zong WX, Edelstein LC, Chen C, Bash J and Gelinas C . (1999). Genes Dev., 13, 382–387.

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Technical assistance was provided by the Morphology Core of the Washington University Digestive Diseases Research Core Center. This work was supported by grants to SJW from the NIH, the Washington University Digestive Diseases Research Core Center (NIH P30-DK52574), the Elsa U Pardee Foundation, the Midwest Stone Institute, and the Goldman Philanthropic Partnerships Culpeper Biomedical Pilot Initiative.

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Correspondence to Steven Jay Weintraub.

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Henderson, C., Zhang, Z., Manson, S. et al. A moderate reduction of Bcl-xL expression protects against tumorigenesis; however, it also increases susceptibility to tissue injury. Oncogene 24, 7120–7124 (2005).

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  • Bcl-xL
  • lung cancer
  • tumorigenesis
  • carcinogen
  • apoptosis
  • tissue injury

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