Bcl-2 differentially targets K-, N-, and H-Ras to mitochondria in IL-2 supplemented or deprived cells: Implications in prevention of apoptosis

IL-2 deprivation triggers apoptosis in the murine T cell line TS1 alpha bet a, a process that can be blocked by overexpression of Bcl-2, Here we show t hat Bcl-2 and Ras proteins interact in mitochondria from TS1 alpha beta cel ls in the presence or absence of IL-2, as evidenced by coimmunoprecipitatio n, All three Ras proteins, K-, N- and H-Ras, interact with Bcl-2; however, their mitochondrial localization is differentially regulated in IL-2-supple mented or -deprived cells, K-Ras is found in mitochondria only in IL-2-supp lemented cells, whereas H-Ras is observed in mitochondria only after IL-2 w ithdrawal. N-Ras is detected in mitochondria under both experimental condit ions. Bcl-2 transfection partially restored K- and N-Ras association with m itochondria in IL-2-deprived cells and rendered H-Ras association independe nt of IL-2 withdrawal. Inhibitors of Ras posttranslational processing did n ot alter the IL-2-induced differential pattern of mitochondrial localizatio n, The processed forms of K- and N-Ras associated with mitochondria, althou gh unprocessed H-Ras was also detected in mitochondria from mevastatin-trea ted cells, These results evidence a distinct behavior among the three Ras p roteins in TS1 alpha beta cells, depending on IL-2 supply, and suggest homo logue-specific roles for Ras proteins in IL-2-dependent events.