INDUCTION OF APOPTOSIS BY THE TRANSCRIPTION FACTOR C-JUN

c-Jun, a signal-transducing transcription factor of the AP-1 family, n ormally implicated in cell cycle progression, differentiation and cell transformation, recently has also been linked to apoptosis, To explor e further the functional roles of c-Jun, a conditional allele was gene rated by fusion of c-Jun with the hormone-binding domain of the human estrogen receptor (ER). Here we demonstrate that increased c-Jun activ ity is sufficient to trigger apoptotic cell death in NIH 3T3 fibroblas ts. c-Jun-induced apoptosis is evident at high serum levels, but is en hanced further in factor-deprived fibroblasts. Furthermore, apoptosis by c-Jun is not accompanied by an increase in DNA synthesis. Constitut ive overexpression of the apoptosis inhibitor protein Bcl-2 delays the c-Jun-mediated cell death, The regions of c-Jun necessary for apoptos is induction include the amino-terminal transactivation and the carbox yterminal leucine zipper domain, suggesting that c-Jun may activate ce ll death by acting as a transcriptional regulator. We further show tha t alpha-fodrin, a substrate of the interleukin 1 beta-converting enzym e (ICE) and CED-3 family of cysteine proteases, becomes proteolyticall y cleaved in cells. undergoing cell death by increased c-Jun activity. Moreover, cell-permeable irreversible peptide inhibitors of the ICE/C ED-3 family of cysteine proteases prevented the cell death.