mcl-1 was identified as an "early-induction" gene that increases in expression during the differentiation of ML-1 human myeloblastic leukemia cells. The mcl-1 gene product proved to be a member of the bcl-2 gene family and, like bcl-2, to have the capacity to promote cell viability. The pattern of expression of mcl-1 has now been characterized, the aim being to determine whether increased expression is consistently associated with differentiation-induction and whether expression is also associated with other changes in proliferative state or cell viability. Expression of the mcl-1 mRNA was found to increase rapidly in ML-1 cells exposed to inducers of monocyte/macrophage differentiation (phorbol esters or lymphocyte conditioned medium), but not cells exposed to an inducer of granulocyte differentiation (retinoic acid). Expression also increased rapidly in response to certain cytotoxic agents (colchicine and vinblastine), but did not increase during serum stimulation or growth-arrest in reduced serum. Increased expression of mcl-1 occurred during the initiation of cell differentiation or death and was not inhibited by cycloheximide, in agreement with the designation of mcl-1 as an early-induction gene. Increased transcription contributed to the in- crease in expression, and turnover of the mcl-1 mRNA was rapid. These findings suggest that mcl-1 may serve as a modulator of cell viability that can undergo rapid upregulation as well as downregulation, with upregulation harbingering the initiation of cell differentiation or death. o 1996 WiIey-Liss, Inc
We discovered mcl-1 during a screen for genes that increase in expression early in leukemic cell differentiation (Kozopas et al., 1993); mcl-1 proved to be a member of the bcl-2 family (Kozopas et al., 1993). bcl-2 was originally discovered as the gene present at the t(14; 18) chromosome translocation breakpoint in follicular lymphoma (Cleary et al., 1986;Tsujimoto et al., 1986); bcl-2 functions t o promote cell viability but does not promote cell proliferation (Craig, 1995;Hockenbery et al., 1990;Nunez et al., 1991;Vaux et al., 1988). We have recently found that mcl-1 can have effects somewhat similar to those of bcl-2, in that mcl-1 can delay c-myc-induced apoptosis in Chinese hamster ovary WHO) cells (Reynolds et al., 1994). Interestingly, the delay produced by mcl-1 is not as prolonged as that produced by bcl-2.
The cell line from which mcl-1 was originally isolated is the ML-1 human myeloblastic leukemia cell line. These cells proliferate at an immature myeloblastic stage, and undergo differentiation along the monocyte/ macrophage pathway upon exposure to 12-O-tetradeca-noylphorbol13-acetate (TPA) (Craig et al., 1984). TPA causes a rapid increase in the mcl-1 mRNA (at 1-3 hours), which is followed by the appearance of differentiating phenotype and the loss of proliferative capac-0