title: Bcl-3 expression promotes cell survival following interleukin-4 deprivation and is controlled by AP1 and AP1-like transcription factors.
abstract: We have analyzed the interleukin-4 (IL-4)-triggered mechanisms implicated in cell survival and show here that IL-4 deprivation induces apoptotic cell death but does not modulate Bcl-2 or Bcl-x expression. Since Bcl-x expression is insufficient to ensure cell survival in the absence of IL-4, we speculate that additional molecules replace the antiapoptotic role of Bcl-2 and Bcl-x in an alternative IL-4-triggered pathway. Cell death is associated with Bcl-3 downregulation and Bcl-3 expression blocks IL-4 deprivation-induced apoptosis, suggesting that Bcl-3 acts as a survival factor in the absence of growth factor. To characterize the IL-4-induced regulation of murine Bcl-3 expression, we cloned the promoter of this gene. Sequencing of the promoter showed no TATA box element but did reveal binding sites for AP1, AP1-like, and SP1 transcription factors. Retardation gels showed that IL-4 specifically induces AP1 and AP1-like binding activity and that mutation of these binding sites abolishes the IL-4-induced Bcl-3 promoter activity, suggesting that these transcription factors are important in Bcl-3 promoter transactivation. IL-4 deprivation induces downregulation of Jun expression and upregulation of Fos expression, both of which are proteins involved in the formation of AP1 and AP1-like transcription factors. Overexpression of Jun family proteins transactivates the promoter and restores Bcl-3 expression in the absence of IL-4 stimulation. Taken together, these data describe a new biological role for Bcl-3 and define the regulatory pathway implicated in Bcl-3 expression.
authors.affiliation: Centro Nacional de Biotecnología, Department of Immunology and Oncology, UAM, E-28049 Madrid, Spain. arebello@cnb.uam.es
authors.forename: A
authors.initials: A
authors.lastname: Rebollo
authors.forename: L
authors.initials: L
authors.lastname: Dumoutier
authors.forename: J C
authors.initials: JC
authors.lastname: Renauld
authors.forename: A
authors.initials: A
authors.lastname: Zaballos
authors.forename: V
authors.initials: V
authors.lastname: Ayllón
authors.forename: C
authors.initials: C
authors.lastname: Martínez-A
mesh_terms: D000818:Animals; D017209:Apoptosis; D000081242:B-Cell Lymphoma 3 Protein; D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D015847:Interleukin-4 / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000166:cytology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors; D051020:bcl-X Protein
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C494812:Bcl2l1 protein, mouse; C000631345:Bcl3 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D015375:Receptors, Interleukin-2; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051020:bcl-X Protein; D015847:Interleukin-4