c-fos gene induction by interleukin 2: identification of the critical cytoplasmic regions within the interleukin 2 receptor beta chain.

Abstract

Interleukin 2 (IL-2) plays a critical role in the growth and differentiation of lymphoid cells. The IL-2 signal is delivered intracellularly by the IL-2 receptor f3 chaln (IL-2Rf); however, the mechanism by which the signal reaches the nucleus remains unclear. In this study, we demonstrate the rapid activation of c-fos protooncogene transcription by IL-2 and provide evidence that the serum-responsive element (SRE) within the c-fos promoter is responsible for the activation in a murine pro-B-cell line, BAF-B03, expressing the human IL2Rl cDNA. Interestingly, the same SRE is also responsible for c-fos gene activation by interleukin 3 or erythropoietin. Further, we show that the activation of c-fos by IL-2 requires defined cytoplasmic regions of IL-2R(-i.e., the "serine-rich" region, which is known to be essential for growth-signal transduction in BAF-B03 cells, and the "acidic region," which is located more distal to the cell membrane. These results indicate the functional importance of the two distinct regions within the IL-2Rfi cytoplasmic domain in IL-2-induced c-fos gene activation and point to a potential role of the acidic region in IL-2 signal transduction that could not be adequately assessed in a previous study.

IL-2 signalling in T and natural killer (NK) cells associated with their class I-non-restricted killing activity

“…only low-affinity IL-2Rs (-chains) [39,40]. It has been demonstrated that the -chain was essential for IL-2 signalling [29,30]. We also observed that protein tyrosine phosphorylation and p21 ras activation were blocked by anti-IL-2R antibody.…”

“…The signal is transduced downstream of the rasdependent [15][16][17] and JAK-STAT [18][19][20][21][22][23][24] pathways, resulting in the expression of proto-oncogenes, such as c-myc, c-fos, and c-jun [29][30][31]. However, neither IL-2 signalling in freshly isolated human lymphocytes nor the intracellular events in LAK induction have been examined.…”

“…These results suggest that the tyrosine phosphorylated proteins are situated rather downstream of p21 ras , if these proteins are associated with the ras-dependent pathway. Following p21 ras activation, the phosphorylation of Raf-1, MAPK kinase, and MAPK must be induced and the signal is finally transduced into the nucleus, resulting in the activation of proto-oncogenes [29][30][31]. However, phosphorylation of MAPK or expression of c-fos-and c-jun-mRNA was not detected.…”

IL‐2‐induced gene expression of protein‐tyrosine phosphatase LC‐PTP requires acidic and serine‐rich regions within IL‐2 receptor β chain

“…The membrane proximal, the serine-rich region of IL-2Rfl is essential for activation of JAK-family PTKs [21] and Src-family Syk [22] as well as for c-myc gene induction. On the other hand, the membrane distal, the acidic region of IL-2R,fl is crucial for activation of Src-family PTKs and for c-fos and c-jun gene induction [23]. To determine the functional subdomain of the IL-2Rfl involved in the LC-PTP gene induction, we examined the LC-PTP gene induction in two BAF-B03 transfectants expressing mutant IL-2Rfls.…”

Transcriptional Regulators and Myelopoiesis: The Role of Serum Response Factor and CREB as Targets of Cytokine Signaling

“…Further support for this is the ability of IL-2 to activate c-fos transcription through activation of SREbinding proteins in BA/F3 cells expressing the IL-2 β receptor. The SRE-binding proteins are similarly activated by IL-3 and EPO, whose receptors share regions of homology with IL-2 in their cytoplasmic domains [61].SRF also plays a role in G-CSF-induced egr-1 expression in the murine myeloid leukemic cell line, NFS60 [19]. We demonstrated that SRF constitutively binds the CArG box of an SRE motif that is flanked by two ETS-protein-binding sites (known as SRE-1) and that lies between nts -418 and -391 of the egr-1 promoter.…”