Bcl-3 expression promotes cell survival following interleukin-4 deprivation and is controlled by AP1 and AP1-like transcription factors

We have analyzed the interleukin-4 (IL-4)-triggered mechanisms implicated i n 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 expressi on is insufficient to ensure cell survival in the absence of IL-4, we specu late that additional molecules replace the antiapoptotic role of Bcl-2 and Bcl-x in an alternative IL-4-triggered pathway. Cell death is associated,vi th Bcl-3 downregulation and Bcl-3 expression blocks IL-4 deprivation-induce d 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 Bc l-3 expression, we cloned the promoter of this gene. Sequencing of the prom oter showed no TATA box element but did reveal binding sites for AP1, AP1-l ike, and SP1 transcription factors. Retardation gels showed that IL-4 speci fically induces AP1 and AP1-like binding activity and that mutation of thes e binding sites abolishes the IL-4-induced Bcl-3 promoter activity, suggest ing that these transcription factors are important in Bcl-3 promoter transa ctivation. IL-4 deprivation induces downregulation of Jun expression and up regulation of Fos expression, both of which are proteins involved in the fo rmation of AP1 and APT-like transcription factors. Overexpression of Jun fa mily 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 B cl-3 expression.