@entity599 mustard (SM) induces vesication via poorly understood pathways. The blisters that are formed result primarily from the detachment of the epidermis from the dermis at the level of the basement membrane. In addition, there is @entity137 to the basal cells, although no careful study has been performed to determine the precise mode of cell death biochemically. We describe here two potential mechanisms by which SM causes basal cell death and detachment: namely, induction of terminal differentiation and apoptosis. In the presence of 100 microM SM, terminal differentiation was rapidly induced in primary @entity1 keratinocytes that included the expression of the differentiation-specific markers K1 and @entity7434 and the cross-linking of the cornified envelope precursor protein involucrin. The expression of the attachment protein, fibronectin, was also reduced in a time- and dose-dependent fashion. Features common to both differentiation and apoptosis were also induced in 100 microM SM, including the rapid induction of @entity876 and the reduction of @entity588 . At higher concentrations of SM (i.e., 300 microM), formation of the characteristic nucleosome-sized DNA ladders, TUNEL-positive staining of cells, activation of the @entity462 protease @entity522 / @entity522 , and cleavage of the death substrate @entity12874 polymerase, were observed both in vivo and in vitro. Both the differentiation and the apoptotic processes appeared to be calmodulin dependent, because the calmodulin inhibitor @entity28397 blocked the expression of the differentiation-specific markers, as well as the apoptotic response, in a concentration-dependent fashion. In addition, the intracellular @entity141 chelator, @entity11008 , blocked the differentiation response and attenuated the apoptotic response. These results suggest a strategy for designing inhibitors of SM vesication via the @entity141 -calmodulin or @entity522 / @entity12982 pathway.

XXXX mustard induces markers of terminal differentiation and apoptosis in keratinocytes via a @entity141 -calmodulin and caspase-dependent pathway.

@entity1 :: ('9606', 'Species') :: ['human'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity'] @entity462 :: ('MESH:D003545', 'Chemical') :: ['cysteine'] @entity588 :: ('596', 'Gene') :: ['Bcl-2'] @entity522 :: ('836', 'Gene') :: ['apopain', 'caspase-3'] @entity12874 :: ('MESH:D011064', 'Chemical') :: ['poly(ADP-ribose)'] @entity12982 :: ('142', 'Gene') :: ['PARP'] @entity876 :: ('7157', 'Gene') :: ['p53'] @entity28397 :: ('MESH:C017967', 'Chemical') :: ['W-7'] @entity141 :: ('CHEBI:29108', 'Chemical') :: ['Ca2+'] @entity599 :: ('MESH:D013455', 'Chemical') :: ['Sulfur'] @entity11008 :: ('MESH:C070379', 'Chemical') :: ['BAPTA-AM'] @entity7434 :: ('3858', 'Gene') :: ['K10']
@entity599 :: (MESH:D013455,Chemical) :: ['Sulfur']
