Abstract
Interleukin-7 (IL-7) is a cytokine that is required for T cell development and survival. The anti-apoptotic function of IL-7 is partly through induction of Bcl-2 synthesis and cytosolic retention of Bax. Here we show that the Bcl-2 homology 3 domain-only protein, Bad, is involved in cell death following IL-7 withdrawal from D1 cells, an IL-7-dependent murine thymocyte cell line. IL-7 stimulation resulted in the inactivation of Bad by phosphorylation at Ser-112, -136, and -155. The phosphoinositide 3-kinase (PI3K)/Akt pathway has been implicated previously in Bad phosphorylation. In response to IL-7, the PI3K/Akt pathway induced phosphorylation at Ser-136 and -155, but Ser-112 was partly independent of the PI3K/Akt pathway, indicating an as yet unknown pathway in this response. Following IL-7 withdrawal, dephosphorylated Bad translocated from cytosol to mitochondria, bound to Bcl-2, and accelerated cell death. Thus, the inactivation of Bad contributes to the survival function of IL-7.
Highlights
The mechanism of the survival effect of IL-7 has been partly attributed to the Bcl-2 family of proteins, which affects mitochondria and endoplasmic reticulum [9, 10]
We evaluated the roles of phosphoinositide 3-kinase (PI3K) and Bad in IL-7 signaling using D1 cells, a murine thymocyte cell line that depends on IL-7 for survival and proliferation
To evaluate the role of the PI3K/Akt pathway in IL-7 signaling, we first investigated whether Akt was activated by IL-7
Summary
The mechanism of the survival effect of IL-7 has been partly attributed to the Bcl-2 family of proteins, which affects mitochondria and endoplasmic reticulum [9, 10]. Beyond 8 weeks of life, Bax deletion no longer protects thymocytes from IL-7R␣ deficiency [18] This suggests that another death mediator in addition to Bax counters Bcl-2 later in life following the loss of an IL-7 signal. Bad is a pro-apoptotic member of the Bcl-2 family and belongs to the group of “BH3 domain-only” proteins that bind to Bcl-2 and block its function. Growth factors such as IL-3 can induce the phosphorylation of Bad at Ser-112, -136, and -155 to promote cell survival [19, 20]. We observed that Bad was inactivated by IL-7, that it was capable of mediating apoptosis in these cells, and that its inactivation was partly through PI3K
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