THE BACULOVIRUS ANTI-APOPTOTIC P35 PROTEIN PROMOTES TRANSFORMATION OFMOUSE EMBRYO FIBROBLASTS

The baculovirus p35 protein is a potent inhibitor of programmed cell d eath induced by a variety of stimuli in insects, nematodes, and mammal ian cell lines. The broad ability of p35 in preventing apoptosis has l ed us to investigate its effect on mouse embryo fibroblasts in vitro a nd in vivo. For this purpose, we have used R- cells (3T3-like fibrobla sts derived from mouse embryos with a targeted disruption of the insul in-like growth factor I receptor (IGF-IR) genes) and R508 cells (deriv ed from R- and with 15 x 10(3) IGF-IRs per cell), Both cell lines grow normally in monolayer, but they do not form colonies in soft agar, an d they are non-tumorigenic in nude mice. We show here that, in additio n to its anti-apoptotic effect, p35 causes transformation of R508 cell s, as evidenced by the following: 1) decreased growth factor requireme nts, 2) ability to form foci in monolayer and colonies in soft agar, a nd 3) ability to form tumors in nude mice. Since R- cells stably trans fected with p35 do not transform, our observations suggest that in add ition to its effect as an inhibitor of apoptosis, the baculovirus p35 protein has transforming potential that requires the presence of the I GF-IR. The possibility that these two properties could be separated wa s confirmed by demonstrating that R508 cells expressing another anti-a poptotic protein, Bcl-2, could not form tumors in nude mice.