A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection.

Abstract

SummaryStimulation of the Fas (APO-1, CD95) receptor, which is present on a variety of cells, usually triggers a process of programmed cell death. Systemic injection of anti-Fas antibody into mice leads to fulminant liver destruction resulting from massive hepatocyte apoptosis, and to rapid death. Hepatocytes bear Fas but do not express Bcl-2, a protein that plays, in a number of conditions, a protective role against apoptosis. We have generated mice whose liver expresses Bcl-2 as the result of a bcl-2 transgene placed under the control of the hepatocyte-specific otl-antitrypsin gene promoter, but is otherwise not distinguishable from that of normal mice. These mice display a marked to almost total resistance to liver damage induced by anti-Fas antibody injection. This protective effect of Bcl-2 occurs in the absence of significant variations, in the stimulated livers, in the level of expression of other proteins also involved in resistance or sensitivity to apoptosis, namely Bcl-x, Bax, Bad, Bak, and p53. Mice with protected livers, however, die almost as rapidly as normal mice, which indicates that acute lethality results from stimulation of Fas receptors present on other target organs or cells.

BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma

“…Thus, mice with homozygous knockout of Bid, or transgenic overexpression of either BCL-2 or BCL-X L in the liver, showed significantly attenuated Fasmediated hepatitis (Lacronique et al, 1996;Rodriguez et al, 1996;de la Coste et al, 1999a;Yin et al, 1999). The present demonstration of better survival of the liver-specific BRE transgenic mice compared with the non-transgenic littermates in the model is consistent with our previous findings in cell lines showing inhibition of t-BID-induced mitochondrial release of proapoptotic proteins by overexpressed BRE (Li et al, 2004).…”

The opposing roles of the Akt and c-Myc signalling pathways in survival from CD95-mediated apoptosis

“…Bcl-2/Bcl-X L proteins are thought to act by suppressing release of intra-mitochondrial cytochrome C which, when liberated into the cytosol, activates caspase-9 (and thereafter downstream caspases) via the intermediary adaptor protein Apaf-1 (Li et al, 1997). Indeed, both we (Hueber et al, 1997) and others (Itoh et al, 1993;Rodriguez et al, 1996) have shown that Bcl-2 proteins do suppress CD95-mediated apoptosis in certain circumstances, so Bad might seem a plausible Akt target common to both c-Myc and CD95 apoptotic pathways. However, there is no obvious molecular mechanism linking anti-apoptotic Bcl-2 family members with the classical type 1 CD95/ FADD/caspase-8 pathway.…”

Bcl-2, Bcl-xL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death

“…Moreover, crossing of bcl-2 transgenic mice onto the Fas/APO-1 (CD95)-de®cient lpr background revealed that gain of Bcl-2 and loss of Fas/APO-1 (CD95) synergise in promoting lymphocyte accumulation, indicating that these two molecules regulate distinct pathways to lymphocyte apoptosis (Reap et al, 1995;Strasser et al, 1995c). Although in certain cell lines and hepatocytes of transgenic mice, Bcl-2 and certain homologues have been documented to provide some measure of protection ( Figure 6) and (Hashimoto et al, 1991;White et al, 1992;Itoh et al, 1993;JaÈ aÈ ttelaÈ et al, 1995;Lacronique et al, 1996;Rodriguez et al, 1996), the e ects have been modest at best. In our experiments, it is clear that levels of expression that a ord substantial protection, in a dose-dependent manner, against serum deprivation or treatment with staurosporine only weakly inhibited death induced by the Fas/APO-1 (CD95) ligand or TNF (for example, compare data for WEHI-164 cells between Figure 3f to data in Figure 6c, and for SKW6 and CH1 cells in Figure 5).…”