A moderate reduction of Bcl-x(L) 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 anti-apoptotic protein Bcl-x(L) would affect tumorigenesis. We chose to study Bcl-x(L) because although bcl-x+/- mice were thought to be phenotypically normal, we and others found that haploinsufficiency for Bcl-x(L) 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-x(L) 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-alpha treatment. These findings are important because they suggest that even minor variations in Bcl-x(L) 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-x(L) activity.
Henderson
Charles Christopher
CC
Division of Urology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Zhang
Zhongqiu
Z
Manson
Scott Ryan
SR
Riehm
Jacob Joseph
JJ
Kataoka
Masaaki
M
Flye
Melvin Wayne
MW
Garbow
Joel Richard
JR
You
Ming
M
Weintraub
Steven Jay
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis; D002492:Central Nervous System Depressants / Q000633:toxicity; D000431:Ethanol / Q000633:toxicity; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006579:Heterozygote; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D014520:Urethane / Q000633:toxicity; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494812:Bcl2l1 protein, mouse; D002492:Central Nervous System Depressants; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D014520:Urethane; D000431:Ethanol