Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine- rich region within IL-2 receptor beta c chain

Abstract

BAG-1 is a Bci-2-binding protein which functions in protection from apoptotic cell death. Here we provide evidence for interleukin-2 (IL-2)-mediated upregulation of BAG-1 expression. In hematopoietic cell line BAF-B03 F7 cells, gene transfer mediated expression of the IL-2R beta c chain is sufficient to confer proliferation and cell survival responses to IL-2. In these IL-2R beta c-expressing cells, BAG-1 mRNA was dramatically induced by IL-2. The IL-2-mediated induction of BAG-1 expression required the activation of tyrosine kinase(s) and was sensitive to rapamycin as the induction of bcl-2 expression was. Analysis of the transfectants which express mutant IL-2R beta c chains or mutant Janus family protein tyrosine kinase Jak3 lacking the kinase domain showed that the IL-2-mediated BAG-1 gene expression required the serinerich region within the IL-2R beta c chain, but Jak3 activation was dispensable. The signaling pathway for BAG-1 gene expression thus highly resembles that for bcl-2 gene expression, strongly suggesting that their induction shares the same signaling pathway. In addition, deletion of the serine-rich region led to loss of IL-2-mediated protection from apoptotic cell death. Taken together, these studies demonstrate that the serine-rich region of the IL-2R beta c chain mediates the coordinated expression of bcl-2 and BAG-1 genes, thereby contributing to suppression of apoptosis.

p53-inducible human homologue of Drosophila seven in absentia (Siah) inhibits cell growth: suppression by BAG-1

“…The interaction of BAG-1 with HGF-and PDGF-receptors has been correlated with enhanced generation of signals that selectively promote cell survival, apparently without influencing the signaling involved in mitogenesis (Bardelli et al, 1996). Moreover, BAG-1 expression is inducibly increased by some growth factors, including IL-2, IL-3 and prolactin, in hematopoietic and lymphoid cells (Adachi et al, 1996;Clevenger et al, 1997), and gene transfermediated elevations in BAG-1 can abrogate growth factor dependence for growth and survival in some circumstances (Clevenger et al, 1997). In addition, we have obtained evidence from immunohistochemical analysis of human tumors that BAG-1 expression is elevated in a significant proportion of breast and prostate adenocarcinomas, compared with normal mammary and prostate epithelial cells (manuscripts submitted).…”

Biological activities of HAP46/BAG‐1

“…Therefore, it will be helpful in the treatment of cancer if levels of HAP46/BAG-1M and HAP50/BAG-1L could be decreased by specific agents or external treatments. Indeed, protein-kinase inhibitors, such as genistein and flavopiridol, and the immunosuppressant rapamycin, downregulate the BAG-1 gene (Adachi et al, 1996;Kullmann et al, 1998;Kitada et al, 2000). However, decreased levels of HAP50/BAG-1L caused HeLa cells to be less sensitive to anticancer drugs (Takahashi et al, 2003).…”