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BAG-1 and Bcl-2 in IL-2 signaling
M Adachi1, T Torigoe, S Takayama
1The First Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan. adachi@sapmed.ac.jp
Insights
Mitogenic cytokines like interleukin-2 (IL-2) promote hematolymphoid cell survival by inhibiting apoptosis. Specific domains of the IL-2 receptor (IL-2R) mediate distinct survival and proliferation signals, crucial for regulating cell numbers.
Area of Science:
- Immunology
- Cell Biology
- Molecular Signaling
Background:
- Cytokines regulate hematolymphoid cell numbers by promoting survival and inhibiting apoptosis.
- Mitogenic cytokines induce proliferation and survival by downregulating programmed cell death.
- Key anti-apoptotic molecules like Bcl-2 and BAG-1 are induced by cytokine signaling.
Purpose of the Study:
- To review the signal transduction pathways of cytokine receptors involved in apoptosis suppression.
- To elucidate the role of specific interleukin-2 receptor (IL-2R) subunits in mediating cellular survival.
- To discuss the segregation of mitogenic and survival signaling pathways.
Main Methods:
- Analysis of cytokine receptor structure-function relationships.
- Investigation of signal transduction pathways in T lymphocytes.
- Review of existing literature on cytokine signaling and apoptosis suppression.
Main Results:
- The serine-rich (S) region of the IL-2R beta c chain is critical for both IL-2-induced proliferation and survival.
- Survival signaling, including bcl-2 and bag-1 gene induction, is mediated by the S region.
- Survival signaling is independent of Jak-family kinase activation and rapamycin sensitivity, segregating from mitogenic signaling.
Conclusions:
- The IL-2R beta c chain contains distinct functional domains for mitogenic and survival signaling.
- Cytokine receptor signaling pathways can be segregated, allowing for differential regulation of proliferation and survival.
- Understanding these pathways is crucial for comprehending hematolymphoid cell number regulation and developing targeted therapies.
Abstract:
Some cytokines can prolong cell survival in hematolymphoid cells and thus may be crucial for regulation of hematolymphoid cell numbers. It has been shown that mitogenic cytokines can induce not only cellular proliferation but also cellular survival by inhibiting apoptosis in hematolymphoid cells. The signals transduced by these cytokines eventually go to the nucleus and induce expression of their specific target genes. In this context, the induction of anti-apoptotic molecules such as Bcl-2 oncoprotein and BAG-1 protein seems to be a key event for the anti-apoptotic function of cytokines. In T lymphocytes, the interaction of interleukin-2 (IL-2) with its receptor (IL-2R) induces both cellular proliferation and cellular survival. The IL-2R consists of three subunits, i.e., IL-2Ralpha, IL-2R(beta)c, and IL-2R(gamma)c chains. Structure-function analysis of the IL-2R(beta)c chain has revealed that there are at least two functional domains within the subunit. The serine-rich (S) region but not the acidic (A) region within the (beta)c chain is responsible for the mitogenic signaling of IL-2R. The S region is also crucial for the cellular survival signaling, which include the induction of anti-apoptotic gene expressions bcl-2 and bag-l. However, the cellular survival signaling is segregated from the mitogenic signaling in independence from the Jak-family protein kinase activation and rapamycin sensitivity. Segregation of the two signaling pathways of a cytokine receptor has also been shown in receptors of the other mitogenic cytokines. Current topics regarding signal transductions of cytokine receptors responsible for the suppression of apoptosis are discussed in this review.