DEFECTIVE TNF-ALPHA-INDUCED APOPTOSIS IN STAT1-NULL CELLS DUE TO LOW CONSTITUTIVE LEVELS OF CASPASES

Signal transducers and activators of transcription (STATs) enhance tra nscription of specific genes in response to cytokines and growth facto rs. STAT1 is also required for efficient constitutive expression of th e caspases Ice, Cpp32, and Ich-l in human fibroblasts. As a consequenc e, STAT1-null cells are resistant to apoptosis by tumor necrosis facto r alpha (TNF-alpha). Reintroduction of STAT1 alpha restored both TNF-a lpha-induced apoptosis and the expression of Ice, Cpp32, and Ich-1. Va riant STAT1 proteins carrying point mutations that inactivate domains required for STAT dimer formation nevertheless restored protease expre ssion and sensitivity to apoptosis, indicating that the functions of S TAT1 required for these activities are different from those that media te induced gene expression.