The human ISG12a gene is a novel caspase dependent and p53 independent pro-apoptotic gene, that is overexpressed in breast cancer

Interferon Stimulated Gene 12a, ISG12a, is a member of a family of small intracellular non-secreted proteins (10–20 kDa), mainly induced by type I IFNs and slightly induced by type II IFN. It has been shown that full length ISG12 (ISG12a) is overexpressed in breast cancer, yet the biological function of ISG12 is largely unknown. Here we show that transient transfection of ISG12a into various mammalian cell lines leads to accumulation of cells initially in the G1 phase of the cell cycle, followed by accumulation of cells in the sub G1 phase, and that cells transfected with ISG12a undergo morphological changes, such as rounding up and detachment from the plate, that are characteristic of apoptosis. Induction of apoptosis by ISG12a was confirmed by Annexin V binding assays and by TUNEL assays. Using general and specific caspase inhibitors, we also showed that ISG12a-induced apoptosis is a caspase dependent, but does not involve p53. Elevation in endogenous ISG12a levels following induction of apoptosis with reagents that induce apoptosis in the intrinsic apoptotic pathway, and reduction in ISG12a-induced apoptosis following co-transfection with Bcl-2, indicated that ISG12a induced apoptosis in the intrinsic apoptotic pathway. Our results suggest a role for the ISG12a gene as a novel pro-apoptotic gene.