Drug transporters are an important part of the defense of cells against 
cytotoxic agents. One major group of transporters is known as multidrug 
resistance associated proteins (MRP; ABCC gene family). The MRPs belong to the 
ATP binding cassette transporter superfamily. One family member, ABCC4 (also 
known as MRP4) functions as a cellular efflux pump for anti-HIV drugs, such as 
9-(2-phoshoenylmethoxyethyl) adenine and azido-thymidine-monophosphate, an 
antiviral nucleotide, ganciclovir-monophosphate, and anti-cancer agents such as 
thiopurines. We isolated a ABCC4 cDNA encoding a non-functional protein, owing 
to an insertion, and subsequently determined the ABCC4 gene structure. This 
analysis revealed that the insertion was attributed to two additional exons that 
would be predicted to produce premature termination codons (PTC) in ABCC4. The 
highly similar mouse Abcc4 gene also contained these exons, which were 
remarkable because their size and sequence identity were much higher than the 
overall similarity between these genes. Further, a comparison of human, monkey 
and rodent ABCC4 genes revealed that these same PTC-producing exons were also 
highly conserved in evolution. As all the ABCC4 mRNA containing these PTC exons 
might produce nonsense mRNA, we further tested the hypothesis that these mRNAs 
were targets of nonsense-mediated mRNA decay (NMD). Protein synthesis inhibition 
selectively stabilized PTC containing ABCC4 transcripts in human, monkey and 
rodent cell lines. Moreover, the amount of PTC-containing ABCC4 transcripts was 
critically dependent upon protein synthesis, as removal of the inhibitor 
dramatically decreased expression, which correlated with the resumption of 
protein synthesis. These are the first studies to indicate that the highly 
conserved PTC exons of the ABCC4 gene may dictate its expression.