Interleukin‐7 regulates c‐myc expression in murine T cells and thymocytes: a role for tyrosine kinase(s) and calcium mobilization

Abstract

Interleukin-7 (IL-7) was originally identified as a pre-B cell growth factor whose proliferating activity has been extended to numerous target cells including T lymphocytes. We investigated c-myc mRNA expression, an oncogene associated with proliferation, in the murine T cell line D10 G4.1 and freshly isolated thymocytes since both target cells proliferate in response to IL-7. We find that blockade of the tyrosine kinase pathway by genistein, a potent tyrosine kinase inhibitor, inhibits both IL-7-dependent D10 G4.1 cell proliferation and c-myc mRNA expression which appears to involve de novo mRNA synthesis and to be under the control of short-lived protein repressor(s). We have also examined possible signal transduction pathways which might regulate c-myc mRNA expression in the murine T cell line. IL-7 biological activity is not affected by stimulation of the protein kinase C pathway by phorbol esters. Thus, IL-7 regulates c-myc mRNA expression in a protein kinase C-independent manner and these data are strengthened by protein kinase C depletion which does not modify IL-7 c-myc mRNA responsiveness. In contrast and independent of protein kinase C activation, intracellular calcium mobilization by means of ionomycin reduces IL-7 induction of c-myc mRNA expression and may represent a physiological mechanism whereby IL-7 bioactivity is regulated. The activity of IL-7 on c-myc mRNA expression has been extended to freshly isolated thymocytes and we find a synergistic effect of IL-7 with concanavalin A. Taken together our results illuminate the molecular mechanism of IL-7 c-myc induction in the T lineage by ascribing a role for tyrosine kinase and increase in intracellular calcium in both IL-7 induced gene induction and cell proliferation.

Superior Parietal Cortex Activation During Spatial Attention Shifts and Visual Feature Conjunction

“…This difference was reflected in a significant task-by-display-size interaction [F(4,56) = 4.47, P < 0.0051 (10).…”

“…The PER protein is predominantly nuclear (5-7) and also accumulates with a circadian rhythm (5,6,8,9). However, PER is most abundant late at night when per RNA levels are low (5,8,9,10). These observations, and the finding that constitutive overexpression of PER protein can substantially diminish the per mRNA rhythm in certain cells of the fly ( l o ) , are consistent with the proposal that PER negatively regulates expression of its own mRNA (3).…”

Tumor-Specific Effector CD8+ T Cells That Can Establish Immunological Memory in Humans after Adoptive Transfer Are Marked by Expression of IL7 Receptor and c-myc

“…Recent studies of primary T cells have suggested a robust physiological role for Myc in global transcriptional amplification (12), proliferation (38), reprogramming of the cellular metabolic state upon T cell activation (39), but paradoxically also increased apoptosis (40). We hypothesize that the overexpression of Myc in our CD8+ effector clones may be balanced by the anti-apoptotic and pro-survival effects of BCL6 and/or IL-7R (41) to direct the memory fate of effector cells. However, further mechanistic studies are necessary to define this interaction.…”

Signal Transduction, Mitotic Catastrophes, and Death in T‐Cell Development

“…Interestingly, it has been shown that c-myc expression in thymocytes can be enhanced by IL-7 in a tyrosine kinase and Ca^"^-dependent manner (Seckinger et al 1994) and that c-myc induces gene expression of the murine p34"''^^ and cyclin-dependent kinase-2 (cdk-2) homologues in murine T lymphocytes . Although c-myc-induced apoptosis can occur at different stages of the cell cycle (reviewed in White 1993), deregulated activation of cdc-2 kinase leads lo activation-induced cell death through a "mitotic-catastrophe" .…”