Characterizing the pro-survival function of the cutA growth arrest specific gene in quiescent chicken embryo fibroblasts

Abstract

Genes expressed during quiescence, known as growth arrest specific (GAS) genes are of great interest due to their ability to prevent a cell from proliferating while enhancing its survivability by maintaining lipid homeostasis amongst other varied mechanisms. In response to nutritional stress, GAS genes may be upregulated, leading to quiescence instead of differentiation or senescence, implying that they are markers of quiescence. A GAS gene of particular interest is cutA. Gene profiling studies investigating gene signatures that are upregulated in response to quiescence inducing environments showed cutA to have a 50-fold increase in expression, one of the strongest responses to contact inhibition from the 28,000 genes that were analyzed. First characterized in Escherichia coli, as a divalent cation tolerance protein, cutA has a highly conserved trimeric structure across species, indicating a potentially fundamental role in cells. In this study, we confirmed the induction of cutA expression in response to oxygen depleted (hypoxia, contact inhibition) conditions that induce cellular quiescence, as well as in response to metal addition. We investigated the effect of aberrant cutA expression on cell proliferation and survival in quiescence by shRNA-mediated downregulation of the gene, which revealed that cutA does have a function in promoting cell survival in quiescence. Based on our findings, we propose a mechanism for the transcriptional activation of cutA in response to quiescent, and in response to metal addition.