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Pamela Eversole–Cire, Francis A. Concepcion, Melvin I. Simon, Shinichi Takayama, John C. Reed, Jeannie Chen; Synergistic Effect of Bcl-2 and BAG-1 on the Prevention of Photoreceptor Cell Death. Invest. Ophthalmol. Vis. Sci. 2000;41(7):1953-1961.
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purpose. Ectopic expression of Bcl-2 in photoreceptors of mice with
retinal degenerative disease slows progression of the disease. BAG-1
has previously been shown to augment the inhibitory effect of Bcl-2 on
programmed cell death in cultured cell systems. This study was designed
to determine whether the coexpression of BAG-1 and Bcl-2 in the
photoreceptors of mice with an autosomal dominant form of retinitis
pigmentosa (RP) would enhance the protective effect provided by Bcl-2
methods. An expression vector using the 5′ regulatory region of the murine opsin
gene was used to target the expression of BAG-1 specifically to
photoreceptor cells of mice. The BAG-1 transgenic mice were crossed to
Bcl-2 transgenics to obtain animals that coexpress the two transgenes
in photoreceptor cells. BAG-1/Bcl-2 animals were then crossed to an RP
mouse model (a transgenic line overexpressing the S334ter rhodopsin
mutant) to assess the effect of coexpression of BAG-1 and Bcl-2 on
retinal degeneration. Morphologic analysis was performed on retinas
isolated at various times after birth to monitor disease progression.
results. High levels of BAG-1 expression resulted in retinal degeneration that
was not prevented by Bcl-2 expression. However, coexpression of
appropriate levels of BAG-1 and Bcl-2 was found to have a profound
inhibitory effect on retinal degeneration caused by overexpression of a
mutant rhodopsin transgene. Whereas expression of Bcl-2 alone was
previously found to delay degeneration of the retina from 2 weeks to
approximately 4 weeks of age, coexpression of BAG-1 and Bcl-2 inhibited
photoreceptor cell death for as long as 7 to 9 weeks.
conclusions. The synergistic effect against photoreceptor cell death produced by the
coexpression of Bcl-2 and BAG-1 indicates that these proteins can
function in concert to prevent cell death. At the correct dosage,
coexpression of Bcl-2 and BAG-1 may serve as a potential means to treat
retinal degenerative diseases.
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