Biomaterial Database

Structural and functional characterization of the mouse multidrug resistance gene family. 1990

R Dhir, and E Buschman, and P Gros

Department of Biochemistry, McGill University, Montreal, Canada.

The mouse multidrug resistance (mdr) gene family is composed of three closely related genes mdr1, mdr2 and mdr3. To clarify the role of these three genes in the emergence of multidrug resistance and to initiate a structure-function analysis of the corresponding proteins, we have isolated full length cDNA clones corresponding to their respective cellular RNA transcripts. Sequence analyses indicate that the three encoded polypeptides are highly similar sharing the same predicted structural features and a high degree of sequence homology (85% to 92%). The three genes are contiguous on a 625 kb chromosomal segment and appear to result from two consecutive gene duplication events. Hybridization studies with gene specific probes in independently derived multidrug resistant cell lines and transfection experiments with full length cDNA clones indicate that mdr1 and mdr3 but not mdr2 overexpression can induce multidrug resistance. In transfected cells, multidrug resistance is linked to a decreased drug accumulation and an concomitant increased ATP-dependent drug efflux. Mutational analysis indicates that both predicted ATP binding domains in mdr1 are absolutely essential for biological activity. The study of chimeric proteins constructed between biologically active mdr1 and inactive mdr2 indicate that both ATP binding domains of mdr2 are functional and suggest that transmembrane domains of mdr1 are essential for the drug resistance phenotype conferred by this protein. Finally, although mdr1 and mdr3 can confer multidrug resistance, drug survival characteristics of mdr1 and mdr3 transfectants indicate that both proteins have overlapping but distinct substrate specificities.

UI	MeSH Term	Description	Entries
D008562	Membrane Glycoproteins	Glycoproteins found on the membrane or surface of cells.	Cell Surface Glycoproteins,Surface Glycoproteins,Cell Surface Glycoprotein,Membrane Glycoprotein,Surface Glycoprotein,Glycoprotein, Cell Surface,Glycoprotein, Membrane,Glycoprotein, Surface,Glycoproteins, Cell Surface,Glycoproteins, Membrane,Glycoproteins, Surface,Surface Glycoprotein, Cell,Surface Glycoproteins, Cell
D010641	Phenotype	The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.	Phenotypes
D002874	Chromosome Mapping	Any method used for determining the location of and relative distances between genes on a chromosome.	Gene Mapping,Linkage Mapping,Genome Mapping,Chromosome Mappings,Gene Mappings,Genome Mappings,Linkage Mappings,Mapping, Chromosome,Mapping, Gene,Mapping, Genome,Mapping, Linkage,Mappings, Chromosome,Mappings, Gene,Mappings, Genome,Mappings, Linkage
D004351	Drug Resistance	Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.	Resistance, Drug
D005786	Gene Expression Regulation	Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.	Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D005796	Genes	A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.	Cistron,Gene,Genetic Materials,Cistrons,Genetic Material,Material, Genetic,Materials, Genetic
D006224	Cricetinae	A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.	Cricetus,Hamsters,Hamster
D000255	Adenosine Triphosphate	An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.	ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D000595	Amino Acid Sequence	The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.	Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia