Bcl-2 Counters Apoptosis by Bax Heterodimerization-dependent and -independent Mechanisms in the T-cell Lineage

Abstract

The effect of the cell death inhibitor Bcl-2 in relation to its capacity to dimerize with apoptosis promoter Bax or its homologs at their physiological expression levels was explored in the T-cell lineage. Transgenic mice expressing a BH1 mutant Bcl-2 (Bcl-2 mI-3), which fails to heterodimerize with proapoptotic members of the Bcl-2 family, such as Bax, were generated. Bcl-2 mI-3 protected immature CD4 ؉ 8 ؉ thymocytes from spontaneous, glucocorticoid and anti-CD3-induced apoptosis and altered T cell maturation, resulting in increased percentages of CD3 hi and CD4 ؊ 8 ؉ thymocytes. In contrast, apoptosis of peripheral T-cells was unaffected by transgene expression. This correlated with their high Bax expression level and insensitivity to the caspase inhibitor, zVAD-fmk, a functional hallmark of Bax-like activity. Thus, within the T-cell lineage Bcl-2 can inhibit apoptosis independent of its association with Bax or its homologs; yet, above a threshold level of their physiologic proapoptotic activity, the capacity of Bcl-2 to heterodimerize with Bax or its homologs appears essential for it to counter cell death.

Antiproliferative effects of zinc-citrate compound on hormone refractory prostate cancer

“…Bax has been shown to suppress the antiapoptosis activity of Bcl-2 by forming a heterodimer with Bcl-2 [17]  . In this study, after the addition of the zinc-citrate compound to HRPC cell line DU145, the expression of Bcl-2 and Bcl-xL was decreased and the expression of Bax was increased.…”

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

“…11,13,21 A sequential combined approach (immunopre- (5 mM), the cytochrome C is localized in the mitochondria, as assessed by Mitotracker dye (red) and anti-cytochrome C antibody (green) by confocal microscopy (left subpanels). With the treatment of 35 mM of D-glucose, the cytochrome C is released into the cytosol (red arrowheads in the middle subpanels), and the release is inhibited by overexpression of Rap1b-pcDNA (right panels).…”

Mutually exclusive expression patterns of Bcl-2 and Par-4 in human prostate tumors consistent with down-regulation of Bcl-2 by Par-4

“…Bcl-2 protein was thought to function by directly binding and inhibiting the function of the pro-apoptotic protein Bax. However, recent studies suggest that while an in vivo competition exists between Bax and Bcl-2, the two proteins may function independently to regulate cell death (Knudson and Korsmeyer, 1997;St Clair et al, 1997;Ishibashi et al, 1998). Bcl-2 and Bax proteins form channels in the mitochondrial membrane and regulate the ion potential and release of the apoptotic marker protein cytochrome C from the mitochondria (Yang and Korsmeyer, 1996).…”