Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5)

Abstract

The control of growth of lymphocyte populations is crucial to the physiological regulation of the immune system, and to the prevention of both leukaemic and autoimmune disease. This control is mediated through modulation of the cell cycle and regulation of cell death. During log-phase growth the rate of proliferation is high and there is a low rate of cell death. As the population density increases, the cell cycle is extended and apoptosis becomes more frequent as the population enters growth arrest. Here, we show that growth-arrest-specific transcript 5 (GAS5) plays an essential role in normal growth arrest in both T-cell lines and non-transformed lymphocytes. Overexpression of GAS5 causes both an increase in apoptosis and a reduction in the rate of progression through the cell-cycle. Consistent with this, downregulation of endogenous GAS5 inhibits apoptosis and maintains a more rapid cell cycle, indicating that GAS5 expression is both necessary and sufficient for normal growth arrest in T-cell lines as well as human peripheral blood T-cells. Control of apoptosis and the cell cycle by GAS5 has significant consequences for disease pathogenesis, because independent studies have already identified GAS5 as an important candidate gene in the development of autoimmune disease.