IL-2-induced signal transduction involves the activation of nuclear NF-kappa B expression.
Using electrophoretic mobility shift assays and DNA-protein cross-linking techniques, we demonstrate that IL-2 binding to functional forms of the human IL-2R activates nuclear expression of the eukaryotic transcription factor NF-kappa B. These inductive effects of IL-2 were observed in three different cellular systems including human Jurkat T cells stably transfected with IL-2R beta cDNA, mouse pro-B BA/F3 cells stably expressing human IL-2R beta chains either alone or in combination with human or murine IL-2R alpha chains, and purified primary resting human T cells constitutively displaying small numbers of IL-2R beta molecules. IL-2 activation of nuclear NF-kappa B expression is regulated in part at a post-translational level, involving the rapid translocation of both the 50- and 65-kDa subunits of NF-kappa B from the cytoplasm to the nucleus. However, IL-2 induction also produced an increase in mRNA for NF-kappa B p105, indicating an additional pretranslational component of regulation. In contrast, IL-2 exerts only minor effects on NF-kappa B p65 mRNA expression. IL-2 induction of NF-kappa B through the IL-2R beta subunit was both correlated with activation of the endogenous IL-2R alpha gene and critically dependent upon the presence of a serine-rich cytoplasmic domain within IL-2R beta (amino acid residues 267-312). This domain has previously been shown to be essential for IL-2-induced cell growth and may correspond to a binding site for an IL-2R beta-associated tyrosine kinase. Together, these findings suggest that NF-kappa B may play an important role as one intracellular second messenger relaying signals from the plasma membrane to cell nucleus that leads to IL-2-induced activation and growth.
Arima
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N
Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Kuziel
W A
WA
Grdina
T A
TA
Greene
W C
WC
D000818:Animals; D001483:Base Sequence; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D011505:Protein-Tyrosine Kinases