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 discovered as an early induction gene during myeloblastic leukemia cell differentiation. This survival protein has the BCL-2 homology (BH) domains 1, 2, and 3 and a C-terminal transmembrane region. We identified a short splicing variant of the MCL-1 mRNA in ... the human placenta encoding a protein, termed MCL-1 short (MCL-1S), with an altered C terminus as compared with the full-length MCL-1 long (MCL-1L), leading to the loss of BH1, BH2, and the transmembrane domains. Analysis of the human MCL-1 gene indicated that MCL-1S results from the splicing out of exon 2 during mRNA processing. MCL-1S, unlike MCL-1L, does not interact with diverse proapoptotic BCL-2-related proteins in the yeast two-hybrid system. In contrast, MCL-1S dimerizes with MCL-1L in the yeast assay and coprecipitates with MCL-1L in transfected mammalian cells. Overexpression of MCL-1S induces apoptosis in transfected Chinese hamster ovary cells, and the MCL-1S action was antagonized by the antiapoptotic MCL-1L. Thus, the naturally occurring MCL-1S variant represents a new proapoptotic BH3 domain-only protein capable of dimerizing with the antiapoptotic MCL-1L. The fate of MCL-1-expressing cells could be regulated through alternative splicing mechanisms and interactions of the resulting anti- and proapoptotic gene products.
Mesh Terms:
Alternative Splicing, Amino Acid Sequence, Animals, Apoptosis, CHO Cells, Cloning, Molecular, Cricetinae, DNA, Complementary, Dimerization, Exons, Expressed Sequence Tags, Gene Library, Humans, Models, Genetic, Molecular Sequence Data, Neoplasm Proteins, Placenta, Precipitin Tests, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, RNA Processing, Post-Transcriptional, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, Two-Hybrid System Techniques
Alternative Splicing, Amino Acid Sequence, Animals, Apoptosis, CHO Cells, Cloning, Molecular, Cricetinae, DNA, Complementary, Dimerization, Exons, Expressed Sequence Tags, Gene Library, Humans, Models, Genetic, Molecular Sequence Data, Neoplasm Proteins, Placenta, Precipitin Tests, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, RNA Processing, Post-Transcriptional, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, Two-Hybrid System Techniques
J. Biol. Chem.
Date: Aug. 18, 2000
PubMed ID: 10837489
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