Diversity in sequence-dependent control of GRO chemokine mRNA half-life

Neutrophil trafficking to sites of injury or infection is regulated, in part, by the closely related GRO family of chemokines (CXCL1, -2, and -3). Expression of the GRO chemokine genes is known to be determined by transcriptional bursts in response to proinflammatory stimulation, but post-transcriptional mechanisms that regulate mRNA half-life are now recognized as important determinants. mRNA half-life is regulated via distinct sequence motifs and sequence-specific, RNA-binding proteins, whose function is subject to regulation by extracellular proinflammatory stimuli. Moreover, such mechanisms exhibit cell-type and stimulus dependency. We now present evidence that in nonmyeloid cells, GRO2 and GRO3 isoforms exhibit at least two patterns of mRNA instability that are distinguished by differential sensitivity to specific mRNA-destabilizing proteins and stimulus-mediated prolongation of mRNA half-life, respectively. Although the 3'UTR regions of GRO2 and GRO3 mRNAs contain multiple AREs, GRO2 has eight AUUUA pentamers, whereas GRO3 has seven. These confer quantitative differences in half-life and show sensitivity for TTP and KSRP but not SF2/ASF. Moreover, these AUUUA determinants do not confer instability that can be modulated in response to IL-1 alpha. In contrast, IL-1 alpha-sensitive instability for GRO2 and GRO3 is conferred by sequences located proximal to the 3' end of the 3'UTR that are independent of the AUUUA sequence motif. These regions are insensitive to TTP and KSRP but show reduced half-life mediated by SF2/ASF. These sequence-linked, post-transcriptional activities provide substantial mechanistic diversity in the control of GRO family chemokine gene expression.