While epidermal growth factor (EGF) is a well known mitogen, high doses of EGF result in a paradoxical apoptotic response in the cells that overexpress EGF receptor such as A431 epidermoid carcinoma cells. EGF-induced apoptosis in A431 cells is dependent upon activation of transcription factor STAT1. In this study, we demonstrate that p38 MAP kinase is another important mediator of EGF-dependent proapoptotic response in A431 cells. By utilizing p38 MAP kinase inhibitors, SB203580 and BIRB0796, we significantly reduced the integral growth-inhibiting as well as pro-apoptotic effects of EGF. Moreover, we observed that inhibition of p38 MAP kinase markedly decreased phosphorylation of tyrosine 701 in STAT1, while neither EGF-induced accumulation nor serine phosphorylation of STAT1 was decreased. We propose that p38 MAP kinase mediates STAT1 tyrosine phosphorylation, thereby enforcing EGF-induced apoptosis. (C) 2012 Elsevier Inc. All rights reserved.