Regulation of mRNA expression through 3’ UTR sequences of IL6 gene in amino acid-deprived HeLa cells
ER stress responses and autophagic responses triggered by amino acid-deprivation of cancer cells activate STAT3 and NF-κB transcriptional factors subsequently to induce IL6 cytokines. Here, it was investigated whether 3’UTR of IL6 mRNA played a role in IL6 induction through cellular stress responses. In the studies with GFP-reporter containing 3’UTR of IL6 mRNA, it was elucidated that 3’UTR contributed to increase of IL6 mRNA after amino acid-starvation, and its motifs seemed to be broadly distributed according to deletion mutants studies of IL6 3’UTR. NF-κB functioned in 3’UTR to partially contribute to stabilization of IL6 mRNA according to knock-down experiments of p65, NF-κB subunit. Finally, treatments of p38 MAP kinase inhibitor, SB203580 markedly blocked mRNA stabilization through 3’UTR as well as IL6 induction after amino acid-starvation, suggesting that p38-MK2/3-TTP pathway is evidently activated and implicated in stabilization of IL6 mRNA during starvation of cancer cells. Conclusively, these studies indicate that stress signals via NF-κB and p38 lead to mRNA stabilization through 3’UTR sequences, and their molecular mechanism would need to be further studied.
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