Induction of apoptosis by the transcription factor c-Jun.
c-Jun, a signal-transducing transcription factor of the AP-1 family, normally implicated in cell cycle progression, differentiation and cell transformation, recently has also been linked to apoptosis. To explore further the functional roles of c-Jun, a conditional allele was generated by fusion of c-Jun with the hormone-binding domain of the human estrogen receptor (ER). Here we demonstrate that increased c-Jun activity is sufficient to trigger apoptotic cell death in NIH 3T3 fibroblasts. c-Jun-induced apoptosis is evident at high serum levels, but is enhanced further in factor-deprived fibroblasts. Furthermore, apoptosis by c-Jun is not accompanied by an increase in DNA synthesis. Constitutive overexpression of the apoptosis inhibitor protein Bcl-2 delays the c-Jun-mediated cell death. The regions of c-Jun necessary for apoptosis induction include the amino-terminal transactivation and the carboxy-terminal leucine zipper domain, suggesting that c-Jun may activate cell death by acting as a transcriptional regulator. We further show that alpha-fodrin, a substrate of the interleukin 1beta-converting enzyme (ICE) and CED-3 family of cysteine proteases, becomes proteolytically cleaved in cells undergoing cell death by increased c-Jun activity. Moreover, cell-permeable irreversible peptide inhibitors of the ICE/CED-3 family of cysteine proteases prevented the cell death.
Bossy-Wetzel
E
E
Unité des Virus Oncogenes, URA 1644 du CNRS, Departement des Biotechnologies, Institut Pasteur, Paris, France.
Bakiri
L
L
Yaniv
M
M
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D003470:Culture Media; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D016350:Leucine Zippers; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation
D003470:Culture Media; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D004247:DNA; D003546:Cysteine Endopeptidases