Acrolein induces activation of the epidermal growth factor receptor of human keratinocytes for cell death

Acrolein, which is a highly reactive formaldehyde generated by lipid peroxi dation, can affect skin and cause various disorders. The effect of exposure of human keratinocytes to acrolein on cell surface-oriented signal transdu ction into cells was examined. Incubation of human keratinocytes with a rel atively low concentration (50 muM) of acrolein caused a prompt and selectiv e induction of tyrosine phosphorylation of the epidermal growth factor rece ptor (EGFR) as a 180-kDa molecule during the period from 5-30 min after the start of incubation. This early event was followed by an increase in the d ensity and number of phosphotyrosine-containing proteins during the period from 60-120 min after the start of incubation. The catalytic activity of EG FR as measured by the levels of autophorphorylation and phosphorylation of an exogenously added substrate, casein, in in vitro kinase assay, greatly i ncreased as early as 1 min after the start of incubation and then decreased gradually 30 min later. MAP family kinases, including ERK, JNK, and p38 ki nase, and the potentially downstream transcription factor c-Jun were all pr omoted for phosphorylation/activation during a period of 5-30 min. Selectiv e prompt phosphorylation/activation of EGFR followed by phosphorylation of MAP family kinases and c-Jun and their blockade by a specific EGFR inhibito r, AG1478, suggested that activation of EGFR is the major, and possibly sin gle, cell surface element for intracellular signal transduction in acrolein -treated cells. Incubation of human keratinocytes with 50 muM of acrolein i nduced atypical apoptosis with morphologic apoptotic features with low-grad e oligonucleoside-sized DNA fragmentation. Partial inhibition of such a cyt opathic effect of acrolein on human keratinocytes by preincubation with AG 1478 suggests the involvement of an EGFR-mediated signal pathway for atypic al apoptosis. These results provide new information on acrolein-induced cel l surface-oriented signal transduction to human keratinocytes, and this inf ormation may be useful for understanding the pathogenesis of a number of sk in diseases in response to environmental acrolein and acrolein-generating u ltraviolet irradiation. J. Cell. Biochem. 81:679-688, 2001. (C) 2001 Wiley- Liss, Inc.