Cell cycle-dependent modulation of alpha-interferon-inducible gene expression and activation of signaling components in Daudi cells

Abstract

To investigate cell cycle-dependent expression of interferon (IFN)-induced genes and signaling pathways, we examined the modulation of IFN-inducible gene expression and p91 activation, and JAK-1 and Tyk-2 kinases' activation in human Burkitt's lymphoma Daudi cells which were synchronized at different points in the cell cycle progression. We observed that each one of 100-, 67-, and 46-kDa 2'-5'-oligoadenylate synthetase (2-5(A)-synthetase) proteins had a unique expression pattern in different phases of the cell cycle which was different from the expression of 2-5(A)-synthetase proteins in exponentially growing Daudi cells. The cell cycle-dependent changes in the overall levels of expression of 2-5(A)-synthetase proteins correlated well with the induction of expression of 2-5(A)-synthetase mRNA as well as the appearance of IFN stimulatory gene factor-3 and expression and activation of p91 in cells released from the G1/S block in the absence of exogenous IFN-alpha. In addition, cells from the G1/S phase exhibited increased tyrosine phosphorylation of JAK-1 and Tyk-2 kinases and p91 by IFN-alpha as compared with asynchronized cells. Enhanced stimulation of activation of JAK-1, Tyk-2, and p91 by IFN-alpha was progressively reduced from G1/S to G2/M to pass G2/M. These findings demonstrate that the levels of constitutive and inducible expression of IFN-alpha-inducible genes, activation of p91, and tyrosine phosphorylation of JAK-1 and Tyk-2 kinases are differentially influenced by the state of the cell cycle.