ACTIVATION OF THE STAT SIGNALING PATHWAY CAN CAUSE EXPRESSION OF CASPASE-1 AND APOPTOSIS

Protein tyrosine kinases activate the STAT (signal transducer and acti vator of transcription) signaling pathway, which can play essential ro les in cell differentiation, cell cycle control, and development. Howe ver, the potential role of the STAT signaling pathway in the induction of apoptosis remains unexplored. Here we show that gamma interferon ( IFN-gamma) activated STAT1 and induced apoptosis in both A431 and HeLa cells, whereas epidermal growth factor (EGF) activated STAT proteins and induced apoptosis in A431 but not in HeLa cells, EGF receptor auto phosphorylation and mitogen-activated protein kinase activation in res ponse to EGF were similar in both cell lines, The breast cancer cell l ine MDA-MB-468 exhibited a similar response to A431 cells. i.e., STAT activation and apoptosis correlatively resulted from EGF or IFN-gamma treatment. In addition, in a mutant A431 cell line in which STAT activ ation was abolished, no apoptosis was induced by either EGF or IFN-gam ma. We further demonstrated that both EGF and IFN-gamma induced caspas e 1 (interleukin-1 beta converting enzyme [ICE]) gene expression in a STAT-dependent manner, IFN-gamma was unable to induce ICE gene express ion and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1- deficient cells (U3A). However, ICE gene expression and apoptosis were induced by IFN-gamma in U3A cells into which STAT1 had been reintrodu ced, Moreover, both EGF-induced apoptosis and IFN-gamma-induced apopto sis were effectively blocked bg Z-Val-Ala-Asp-fluoromethylketone (ZVAD ) in all the cells tested, and studies from ICE-deficient cells indica ted that ICE gene expression mas necessary for IFN-gamma-induced apopt osis, We conclude that activation of the STAT signaling pathway can in duce apoptosis through the induction of ICE gene expression.