A moderate reduction of Bcl-x(L) expression protects against tumorigenesis; however, it also increases susceptibility to tissue injury. Oncogene 2005 Oct 27;24(47):7120-4
Date
07/12/2005Pubmed ID
16007126DOI
10.1038/sj.onc.1208887Scopus ID
2-s2.0-27644564949 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
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.
Author List
Henderson CC, Zhang Z, Manson SR, Riehm JJ, Kataoka M, Flye MW, Garbow JR, You M, Weintraub SJMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Apoptosis
Central Nervous System Depressants
Ethanol
Fibroblasts
Heterozygote
Liver
Lung Neoplasms
Mice
Mice, Knockout
Proto-Oncogene Proteins c-bcl-2
Tumor Necrosis Factor-alpha
Urethane
bcl-X Protein
