REGULATION OF CELL-GROWTH BY IL-2 - ROLE OF STAT5 IN PROTECTION FROM APOPTOSIS BUT NOT IN CELL-CYCLE PROGRESSION

Cytokines play an essential role in the regulation of lymphocyte survi val and growth, We have analyzed the pathways activated by IL-2 that l ead to protection from apoptosis and cell proliferation. IL-2 can act as a long-term growth factor in 32D cells expressing the wild-type hum an (hu)IL-2R beta, By contrast, cells expressing a truncated form of t he huIL-2R beta, which is able to induce Bcl-2 and c-myc expression bu t not STAT5 activation, were not protected from apoptosis by IL-2; con sequently, they could not be grown long term in the presence of IL-2, However, IL-2 promoted cell cycle progression in cells bearing the tru ncated huIL-2R beta with percentages of viable cells in the G(0)/G(1), S, and G(2)/M phases similar to cells expressing the wild-type huIL-2 R beta. Transplantation of a region from the erythropoietin receptor, which contains a docking site for STAT5 (Y343) to the truncated huIL-2 R beta, restored the ability of IL-2 to signal both activation of STAT 5 and protection from apoptosis, By contrast, transplantation of a reg ion from the hulL-4R alpha containing STAT6 docking sites did not conf er protection from apoptosis. These results indicate that the IL-2-ind uced cell cycle progression can be clearly distinguished from protecti on from apoptosis and that STAT5 participates in the regulation of apo ptosis.