Full length Mcl-1 is an anti-apoptotic protein consisting of two closely migrating 42/40 kDa species. We now investigated the relationship of these isoforms to the expression of cell cycle stimulatory (cyclin A) and inhibitory (p21WAF1) proteins and to the induction of apoptosis in wt p53 MCF-7 and mutant p53 SKBR3 human breast carcinomas. The latter cells exhibited lower 42 kDa Mcl-1, higher expression of cyclin A relative to that of p21WAF1, and apoptosis in response to okadaic acid, a phosphatase 1/2A inhibitor. The proteasome inhibitor MG-115 selectively increased expression of the 40 kDa Mcl-1 isoform and induced p21WAF1, but also promoted preferential apoptosis in SKBR3 cells. Neither okadaic acid nor MG-1 15 caused comparable effects in MCF-7 cells. However, vanadate or acetyl furanonaphthoquinone induced the 40 kDa Mcl-1 and greater Jun kinase (JNK) phosphorylation without apoptosis-associated PARP fragmentation in MCF-7 cells. Our data suggest that the higher susceptibility of SKBR3 cells to undergo apoptosis may be partly due to their greater proliferative potential (cyclin A), low expression of the anti-apoptotic 42 kDa Mcl-1 isoform, and suboptimal JNK activation in response to stress. (C) 2002 Elsevier Science (USA). All rights reserved.