Growth factor stimulation induces cell survival by c-Jun. ATF2-dependent activation of Bcl-XL.
Growth factor stimulation induces c-Jun-dependent survival of primary endothelial cells. However, the mechanism of c-Jun anti-apoptotic activity has not been identified. We here demonstrate that in response to growth factor treatment, primary human endothelial cells as well as mouse fibroblasts respond with an increased expression of c-Jun that forms a complex with ATF2. This complex activates the expression of the anti-apoptotic protein Bcl-X(L). By site-directed mutagenesis experiments, we identified two AP-1-binding sites located within the proximal promoter of the Bcl-X gene. Site-directed mutagenesis demonstrated that these AP-1 sites are required for the transcriptional activation of the promoter. Chromatin immunoprecipitation experiments show that in response to growth factor treatment, the heterodimer c-Jun.ATF2 binds to these functional AP-1 sites. Silencing of either c-Jun or ATF2 demonstrated that both nuclear factors are required for the activation of the proximal Bcl-X promoter. Taken together, our experiments provide evidence that growth factor-independent signaling pathways converge in the formation of an active c-Jun.AFT2 dimer, which induces the expression of the anti-apoptotic factor Bcl-X(L) that mediates a pro-survival response.
Salameh
Ahmad
A
Dipartimento di Biologia Molecolare, Universita' di Siena, 53100 Siena, Italy.
Galvagni
Federico
F
Anselmi
Francesca
F
De Clemente
Caterina
C
Orlandini
Maurizio
M
Oliviero
Salvatore
S
D051698:Activating Transcription Factor 2 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D036341:Intercellular Signaling Peptides and Proteins; D018808:Transcription Factor AP-1; D051020:bcl-X Protein; D048031:JNK Mitogen-Activated Protein Kinases