| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Papers In Press, published online ahead of print May 22, 2003
Medical Science Division, Fox Chase Cancer Center, Phildadelphia, PA 19111
Corresponding Author: GD_Kruh{at}fccc.edu
MRP8 (ABCC11) is a recently identified cDNA that has been assigned to the MRP family of ATP-binding cassette transporters, but whose functional characteristics have not been determined. Here we examine the functional properties of the protein using transfected LLC-PK1 cells. It is shown that ectopic expression of MRP8 reduces basal intracellular levels of cAMP and cGMP, and enhances cellular extrusion of cyclic nucleotides following stimulation with forskolin or SIN-1A, respectively. Analysis of the sensitivity of MRP8 overexpressing cells revealed that they are resistant to a range of clinically relavent nucleotide analogs, including the anticancer fluoropyrimidines 5'-fluorouracil (~3-fold), 5'-fluoro-2'-deoxyuridine (~5-fold) and 5'-fluoro-5'-deoxyuridine (~3-fold), the anti-HIV agent 2',3'-dideoxycytidine (~6-fold) and the anti-hepatitis B agent 9'-(2'-phosphonylmethoxynyl) adenine (PMEA, ~5-fold). By contrast, increased resistance was not observed for several natural product chemotherapeutic agents. In accord with the notion that MRP8 functions as a drug efflux pump for nucleotide analogs, MRP8-transfected cells exhibited reduced accumulation and increased efflux of radiolabeled PMEA. In addition, it is shown by the use of in vitro transport assays that MRP8 is able to confer resistance to fluoropyrimidines by mediating the MgATP-dependent transport of 5'-fluoro-2'-deoxyuridine monophosphate, the cytoxic intracellular metabolite of this class of agents, but not of 5'-fluorouracil or 5'-fluoro-2'-deoxyuridine. It is concluded that MRP8 is an amphipathic anion transporter that is able to efflux cAMP and cGMP, and to function as a resistance factor for commonly employed purine and pyrimidine nucleotide analogs.
J. Biol. Chem, 10.1074/jbc.M304059200
Submitted on April 17, 2003
Revised on May 20, 2003
Accepted on May 22, 2003
MRP8 (ABCC11) is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines, 2'3'-dideoxycytidine and 9'-(2'-phosphonylmethoxyethyl)-adenine
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  C. D. Cropp, T. Komori, J. E. Shima, T. J. Urban, S. W. Yee, S. S. More, and K. M. Giacomini Organic Anion Transporter 2 (SLC22A7) Is a Facilitative Transporter of cGMP Mol. Pharmacol., April 1, 2008; 73(4): 1151 - 1158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Honorat, A. Mesnier, J. Vendrell, J. Guitton, I. Bieche, R. Lidereau, G. D Kruh, C. Dumontet, P. Cohen, and L. Payen ABCC11 expression is regulated by estrogen in MCF7 cells, correlated with estrogen receptor {alpha} expression in postmenopausal breast tumors and overexpressed in tamoxifen-resistant breast cancer cells Endocr. Relat. Cancer, March 1, 2008; 15(1): 125 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. P. Lin, Y.-L. Zhu, D. R. Johnson, K. P. Rice, T. Nottoli, B. C. Hains, J. McGrath, S. G. Waxman, and A. C. Sartorelli Disruption of cAMP and Prostaglandin E2 Transport by Multidrug Resistance Protein 4 Deficiency Alters cAMP-Mediated Signaling and Nociceptive Response Mol. Pharmacol., January 1, 2008; 73(1): 243 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Willoughby and D. M. F. Cooper Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains Physiol Rev, July 1, 2007; 87(3): 965 - 1010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Oguri, Y. Bessho, H. Achiwa, H. Ozasa, K. Maeno, H. Maeda, S. Sato, and R. Ueda MRP8/ABCC11 directly confers resistance to 5-fluorouracil Mol. Cancer Ther., January 1, 2007; 6(1): 122 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. G. Deeley, C. Westlake, and S. P. C. Cole Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins. Physiol Rev, July 1, 2006; 86(3): 849 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Andric, T. S. Kostic, and S. S. Stojilkovic Contribution of Multidrug Resistance Protein MRP5 in Control of Cyclic Guanosine 5'-Monophosphate Intracellular Signaling in Anterior Pituitary Cells Endocrinology, July 1, 2006; 147(7): 3435 - 3445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dallas, D. S. Miller, and R. Bendayan Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol. Rev., June 1, 2006; 58(2): 140 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Maher, A. L. Slitt, N. J. Cherrington, X. Cheng, and C. D. Klaassen TISSUE DISTRIBUTION AND HEPATIC AND RENAL ONTOGENY OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) FAMILY IN MICE Drug Metab. Dispos., July 1, 2005; 33(7): 947 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pratt, R. L. Shepard, R. A. Kandasamy, P. A. Johnston, W. Perry III, and A. H. Dantzig The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites Mol. Cancer Ther., May 1, 2005; 4(5): 855 - 863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-S. Chen, Y. Guo, M. G. Belinsky, E. Kotova, and G. D. Kruh Transport of Bile Acids, Sulfated Steroids, Estradiol 17-{beta}-D-Glucuronide, and Leukotriene C4 by Human Multidrug Resistance Protein 8 (ABCC11) Mol. Pharmacol., February 1, 2005; 67(2): 545 - 557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. M. H. Van Aubel, P. H. E. Smeets, J. J. M. W. van den Heuvel, and F. G. M. Russel Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites Am J Physiol Renal Physiol, February 1, 2005; 288(2): F327 - F333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Michael and M.M. Doherty Tumoral Drug Metabolism: Overview and Its Implications for Cancer Therapy J. Clin. Oncol., January 1, 2005; 23(1): 205 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. Annereau, G. Szakacs, C. J. Tucker, A. Arciello, C. Cardarelli, J. Collins, S. Grissom, B. R. Zeeberg, W. Reinhold, J. N. Weinstein, et al. Analysis of ATP-Binding Cassette Transporter Expression in Drug-Selected Cell Lines by a Microarray Dedicated to Multidrug Resistance Mol. Pharmacol., December 1, 2004; 66(6): 1397 - 1405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-L. Xu, H. M. Wolde, V. Gavrilyuk, V. L. Baughman, and D. A. Pelligrino cAMP modulates cGMP-mediated cerebral arteriolar relaxation in vivo Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2501 - H2509. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Hopper-Borge, Z.-S. Chen, I. Shchaveleva, M. G. Belinsky, and G. D. Kruh Analysis of the Drug Resistance Profile of Multidrug Resistance Protein 7 (ABCC10): Resistance to Docetaxel Cancer Res., July 15, 2004; 64(14): 4927 - 4930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dallas, L. Schlichter, and R. Bendayan Multidrug Resistance Protein (MRP) 4- and MRP 5-Mediated Efflux of 9-(2-Phosphonylmethoxyethyl)adenine by Microglia J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1221 - 1229. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
