MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1,encodes a proapoptotic protein possessing only the BH3 domain

MCL-1 (myeloid cell leukemia-1) is an antiapoptotic BCL-2 family protein di scovered as an early induction gene during myeloblastic leukemia cell diffe rentiation. This survival protein has the BCL-2 homology (BH) domains 1, a, and 3 and a C-terminal transmembrane region. We identified a short splicin g variant of the MCL-1 mRNA in the human placenta encoding a protein, terme d MCL-1 short (MCL-1S), with an altered C terminus as compared with the ful l-length MCL-1 long (MCL-1L), leading to the loss of BH1, BH2, and the tran smembrane domains. Analysis of the human MCL-1 gene indicated that MCL-1S r esults from the splicing out of exon 2 during mRNA processing. MCL-1S, unli ke MCL-1L, does not interact with diverse proapoptotic BCL-2-related protei ns in the yeast two-hybrid system. In contrast, MCL-1S dimerizes with MCL-1 L in the yeast assay and coprecipitates with MCL-1L in transfected mammalia n cells. Overexpression of MCL-1S induces apoptosis in transfected Chinese hamster ovary cells, and the MCL-1S action was antagonized by the antiapopt otic MCL-1L. Thus, the naturally occurring MCL-1S variant represents a new proapoptotic BH3 domain-only protein capable of dimerizing with the antiapo ptotic MCL-1L. The fate of MCL-1-expressing cells could be regulated throug h alternative splicing mechanisms and interactions of the resulting anti- a nd proapoptotic gene products.