Analysis of the intron-exon organization of the human multidrug-resistance protein gene (MRP) and alternative splicing of its mRNA.
Overexpression of multidrug-resistance protein (MRP) and P-glycoprotein confers similar but not identical multidrug-resistance phenotypes. However, unlike P-glycoprotein, which comprises two membrane-spanning domains (MSDs) and two nucleotide-binding domains, MRP contains a third NH2-proximal MSD, a feature now identified in several other ATP-binding cassette transmembrane transporters. MRP is located on chromosome 16 at band 13.1 close to the short-arm breakpoint of the pericentric inversion associated with the M4Eo subclass of acute myeloid leukemia. We have defined the intron-exon structure of MRP and characterized a number of splicing variants of MRP mRNA. The gene spans at least 200 kb. It contains 31 exons and a high proportion of class 0 introns, alternative splicing of which results in significant levels of variant transcripts that maintain the original open reading frame of MRP mRNA. Analyses of the conservation of intron-exon organization and protein primary structure suggest that the MRP-related transporters evolved from a common ancestor shared with the cystic fibrosis transmembrane conductance regulator, by fusion with one or more genes encoding polytopic membrane proteins.
Grant
C E
CE
Cancer Research Laboratories, Queen's University, Kingston, Ontario, K7L 3N6, Canada.
Kurz
E U
EU
Cole
S P
SP
Deeley
R G
RG
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D019143:Evolution, Molecular; D005091:Exons; D019450:Genes, MDR; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015183:Restriction Mapping; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D018528:ATP-Binding Cassette Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004247:DNA; D017931:DNA Primers; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C505032:CFTR protein, human