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.

Bcl‐3 is an interleukin‐1–responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene

“…In contrast to reports from other laboratories (27, 31, 32), we did not find that inhibition of Bcl‐3 expression caused increased programmed cell death in SW‐1353 cells. This may be due to the fact that we were able to see substantial MMP‐1 inhibition without complete ablation of Bcl‐3 gene expression (Figure 3).…”

Regulation of monocyte gene expression by the extracellular matrix and its functional implications

“…It has been shown that NF‐κB activation initiates a response that blunts the apoptotic action of several agonists of cell death (77,78). Several of the NF‐κB‐regulated genes induced by matrix attachment have antiapoptotic function: manganese superoxide dismutase (MnSOD) is important in the cellular defense against O 2 – as it catalyzes the conversion of O 2 – to H 2 O 2 and O 2 (79); expression of the zinc finger protein, A20, has been shown to protect cells from cytokine‐induced apoptosis (80), and Bcl‐3 expression promotes cell survival (81). Other matrix‐regulated genes not linked to NF‐κB activation may also play a role in preventing apoptosis.…”

Rhomboid domain containing 1 inhibits cell apoptosis by upregulating AP‐1 activity and its downstream target Bcl‐3

“…Furthermore, the AP-1 binding sites were critical in the Bcl-3 promoter activation, and their mutations abrogate the promoter's activity. The JUN proteins, which are involved in the formation of AP-1 transcription factors, play an important role in the IL-4-induced Bcl-3 expression [16]. Several studies have indicated that the c-Jun activation may be critical as a determinant of the functional outcome of the stress response, especially UV-induced cell death, so cell apoptosis was induced by UV irradiation in our experiments.…”

“…AP-1 transcription factors have also been implicated in the control of cell death and survival, and the consequence of AP-1 activation seems to be cell type specific. It is reported that AP-1 induces apoptosis in the nervous system, and it blocks apoptosis in IL-4-deprived T cells by upregulating the expression of an anti-apoptotic protein, Bcl-3 [16]. The different functions of AP-1 in the regulation of cell apoptosis could be explained by the regulation of different downstream target genes.…”