OMIM Result

*605250 Links

ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 4; ABCC4

Alternative titles; symbols
MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 4; MRP4
MULTISPECIFIC ORGANIC ANION TRANSPORTER B; MOATB

Gene map locus 13q32

TEXT

Cancer cells that overproduce drug-transporting proteins may become resistant to a wide spectrum of drugs with different structures or cellular targets, a phenomenon called multidrug resistance (MDR). MDR/ATP-binding cassette (ABC) membrane proteins are involved in energy-dependent transport of a wide variety of substrates.

By EST database searching with N-terminal PGY1 (ABCB1; 171050) and CFTR (602421) as probes, Allikmets et al. (1996) isolated 21 cDNAs, including a cDNA encoding a 65-amino acid fragment of ABCC4. Using a similar strategy with C-terminal MRP1 (ABCC1; 158343) and CMOAT (ABCC2; 601107) as probes, Kool et al. (1997) obtained cDNAs encoding the C-terminal portion of MRP3 (ABCC3; 604323), ABCC4, and MRP5 (ABCC5; 605251). By degenerative PCR based on the N-terminal sequences of MRP1, followed by plaque hybridization of breast and ovarian bacteriophage libraries, Lee et al. (1998) obtained a cDNA encoding ABCC4, which they termed MOATB. Sequence analysis predicted that the 1,325-amino acid protein, like other ABC transporters, contains nucleotide-binding folds and 12 transmembrane-spanning helices in 2 hydrophobic domains. Northern blot analysis revealed ubiquitous expression of an approximately 6.0-kb transcript that is highest in prostate and lowest in liver and peripheral blood leukocytes (Lee et al., 1998). RNase protection analysis showed only low level expression in a few tissues (Kool et al., 1997). Unlike ABCC2, which is overexpressed in several MDR cell lines, ABCC3 and ABCC5 are overexpressed in only a few such cell lines, and ABCC4 is overexpressed in none (Kool et al., 1997).

Schuetz et al. (1999) found that MRP4 confers resistance to acyclic nucleoside monophosphates, such as 9-(2-phosphonylmethoxyethyl)guanine (PMEG), and to the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine (PMEA).

Lamba et al. (2003) isolated an ABCC4 cDNA encoding a nonfunctional protein, due to an insertion, and subsequently determined the ABCC4 gene structure. The insertion was attributed to 2 additional exons that produced premature termination codons (PTCs). The exons, designated 1a and 1b, were 113 and 153 bp in length, respectively. A comparison of human, monkey, and rodent ABCC4 genes revealed that these same PTC-producing exons were also highly conserved in evolution. In vitro inhibition of protein synthesis (using puromycin or anisomycin) selectively reduced nonsense-mediated mRNA decay of PTC-containing ABCC4 transcripts in all cell lines tested. Lamba et al. (2003) concluded that the highly conserved PTC-containing exons of the ABCC4 gene may dictate its expression.

By radiation hybrid analysis, Kool et al. (1997) mapped the ABCC4 gene to chromosome 13. Using FISH, Lee et al. (1998) refined the localization to 13q32.

REFERENCES

1. Allikmets, R.; Gerrard, B.; Hutchinson, A.; Dean, M. :: Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum. Molec. Genet. 5: 1649-1655, 1996.
PubMed ID : 8894702
2. Kool, M.; de Haas, M.; Scheffer, G. L.; Scheper, R. J.; van Eijk, M. J.; Juijn, J. A.; Baas, F.; Borst, P. :: Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 57: 3537-3547, 1997.
PubMed ID : 9270026
3. Lamba, J. K.; Adachi, M.; Sun, D.; Tammur, J.; Schuetz, E. G.; Allikmets, R.; Schuetz, J. D. :: Nonsense mediated decay downregulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codons. Hum. Molec. Genet. 12: 99-109, 2003.
PubMed ID : 12499391
4. Lee, K.; Belinsky, M. G.; Bell, D. W.; Testa, J. R.; Kruh, G. D. :: Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter. Cancer Res. 58: 2741-2747, 1998.
PubMed ID : 9661885
5. Schuetz, J. D.; Connelly, M. C.; Sun, D.; Paibir, S. G.; Flynn, P. M.; Srinivas, R. V.; Kumar, A.; Fridland, A. :: MRP4: a previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nature Med. 5: 1048-1051, 1999.
PubMed ID : 10470083

CONTRIBUTORS

George E. Tiller - updated : 10/26/2004
Victor A. McKusick - updated : 9/1/2000

CREATION DATE

Paul J. Converse : 8/31/2000

EDIT HISTORY