ISOFORM-SPECIFIC FUNCTIONS OF C-ABL - TYPE-I IS NECESSARY FOR DIFFERENTIATION, AND TYPE-IV IS INHIBITORY TO APOPTOSIS

The c-abl proto-oncogene is expressed ubiquitously during development. There are two predominant isoforms, type I and type IV, Their biologi cal functions in cell growth and development are unknown. To examine t heir respective biological roles, we transduced 70Z/3 lymphoid cells w ith antisense sequences specific to each respective isotype. When the cells were incubated with antisense oligonucleotides against type IV c -abl but not against type I c-abl, induction of apoptosis was observed , as measured by either DNA fragmentation, cell proliferation, or colo ny formation, Immunoprecipitation showed that antisense-treated cells had reduced amounts of c-abl as compared to the untreated cells. When stimulated with lipopolysaccharide (LPS), 70Z/3 cells underwent prolif eration and differentiation, When antisense oligonucleotides against t ype IV were added to the cell cultures, with LPS stimulation, inductio n of apoptosis continued to occur. When antisense oligonucleotides aga inst type I were added in the cultures, in the presence of LPS, cell d ifferentiation was inhibited, but cell proliferation continued to occu r, This inhibition of differentiation was evident by a lack of immunog lobulin light chain production by cells that otherwise would produce i mmunoglobulin when they are stimulated with LPS, These data therefore show that type I c-abl allows cell differentiation to occur, whereas t ype IV c-abl suppresses apoptosis.