SUPPRESSION OF SIGNALING THROUGH TRANSCRIPTION FACTOR NF-AT BY INTERACTIONS BETWEEN CALCINEURIN AND BCL-2

It is not known how the protein Bcl-2 inhibits cell death induced by c alcium signalling and growth-factor withdrawal(1-3). Here we report th at Bcl-2 forms a tight complex with calcineurin, resulting in the targ eting of calcineurin to Bcl-2 sites on cytoplasmic membranes, and show that this interaction is dependent on the BH4 domain of Bcl-2. Calcin eurin bound to Bcl-2 is an active phosphatase but is unable to promote the nuclear translocation of NF-AT, a transcription-factor required f or induction of interleukin-2 expression, suggesting a mechanism by wh ich Bcl-2 suppresses NF-AT activity(4). We also show that Bar, a pro-a poptotic member of the Bcl-2 family, interferes with interactions betw een calcineurin and Bcl-2. We propose that the ability of Bcl-2 to blo ck NF-AT signalling is due to the sequestering of active calcineurin t o the same domain of Bcl-2 which associates with Rad-1 (ref. 5), and t hat calcineurin may act in Bcl-2-regulated functions.