bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations.

Abstract

Apoptosis of photoreceptors occurs infrequently in adult retina but can be triggered in inherited and environmentally induced retinal degenerations. The protooncogene bcl-2 is knoWn to be a potent regulator of cell survival in neurons. We created lines oftransgenic mice overexpressing bcl-2 to test for its ability to increase photoreceptor survival. Bcl-2 increased photoreceptor survival in mice with retinal degeneration caused by a defective opsin or cGMP phosphodiesterase. Overexpression of Bcl-2 in normal photoreceptors also decreased the damaging effects of constant light exposure. Apoptosis was induced in normal photoreceptors by very high levels of bcl-2. We conclude that bcl-2 is an important regulator of photoreceptor cell death in retinal degenerations.

Overexpression of Bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice

“…Based on experimental overexpression in transgenic mice, this has so far been demonstrated for lymphoid cells (McDonnell et al, 1989), for neurons of the central nervous system (Martinou et al, 1994), for hepatocytes (Lacronique et al, 1996) and, recently, for retinal photoreceptors (Chen et al, 1996). In this paper we describe transgenic mice which overexpress Bcl-2 under the control of the murine WAP promoter in their lactating mammmary glands.…”

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

“…The role of Bcl-2 in retina is unclear. Chen et al (1996) showed that in transgenic mice, expression of bcl-2 under the control of an opsin promoter resulted in partial, temporary preservation of photoreceptors in three types of retinal degenerations, whereas other studies have shown no signi®cant reduction in the rate or extent of apoptosis in photoreceptors (Papermaster, 1997). Furthermore, both increases and decreases in bcl-2 levels have been described after various injuries (Montpied et al, 1993;Gillardon et al, 1995).…”

“…Despite distinct functions, BcL-2 and BcL-x have both been found to inhibit the release of cytochrome c, which is associated with the activation of caspase 3 from mitochondria. In transgenic mice expressing the Bcl-2 gene with light-damage, and in degenerating rd mice, there is a partial and temporary preservation of the retina, suggesting a role for antiapoptotic members of the Bcl-2 protein family in the survival of retinal neurons (Chen et al, 1996). Thus, these two anti-apoptotic factors seems to be good candidates for mediating FGF2 survival activity in RPE cells.…”

“…In retinal dystrophy in rat, cell apoptosis is prevented by a single subretinal injection of exogenous FGF2, demonstrating that FGF2 can act as a survival-promoting trophic factor in the retina in vivo (Faktorovich et al, 1990). In culture, RPE cells produce FGF1 and FGF2 (Chen et al, 1996), FGF high a nity receptors (FGFR) and in particular FGFR1 (Guillonneau et al, 1997). In growing RPE cells, ERKs are rapidly and transiently activated in response to exogenous FGFs (Malecaze et al, 1993).…”

Apoptosis of the mammalian retina and lens

“…Chen et al (1996) made transgenic mice bearing a mutated opsin gene that induces an apoptotic degeneration of photoreceptors and crossed them to other transgenic mice expressing bcl-2 under the control of a murine opsin promoter fragment. This cross results in partial and temporary preservation of the rods and cones expressing high levels of bcl-2.…”