title: A novel mechanism of sodium iodide symporter repression in differentiated thyroid cancer.
abstract: Differentiated thyroid cancers and their metastases frequently exhibit reduced iodide uptake, impacting on the efficacy of radioiodine ablation therapy. PTTG binding factor (PBF) is a proto-oncogene implicated in the pathogenesis of thyroid cancer. We recently reported that PBF inhibits iodide uptake, and have now elucidated a mechanism by which PBF directly modulates sodium iodide symporter (NIS) activity in vitro. In subcellular localisation studies, PBF overexpression resulted in the redistribution of NIS from the plasma membrane into intracellular vesicles, where it colocalised with the tetraspanin CD63. Cell-surface biotinylation assays confirmed a reduction in plasma membrane NIS expression following PBF transfection compared with vector-only treatment. Coimmunoprecipitation and GST-pull-down experiments demonstrated a direct interaction between NIS and PBF, the functional consequence of which was assessed using iodide-uptake studies in rat thyroid FRTL-5 cells. PBF repressed iodide uptake, whereas three deletion mutants, which did not localise within intracellular vesicles, lost the ability to inhibit NIS activity. In summary, we present an entirely novel mechanism by which the proto-oncogene PBF binds NIS and alters its subcellular localisation, thereby regulating its ability to uptake iodide. Given that PBF is overexpressed in thyroid cancer, these findings have profound implications for thyroid cancer ablation using radioiodine.
authors.affiliation: School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham B15 2TH, UK.
authors.forename: Vicki E
authors.initials: VE
authors.lastname: Smith
authors.forename: Martin L
authors.initials: ML
authors.lastname: Read
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Turnell
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Watkins
authors.forename: John C
authors.initials: JC
authors.lastname: Watkinson
authors.forename: Greg D
authors.initials: GD
authors.lastname: Lewy
authors.forename: Jim C W
authors.initials: JC
authors.lastname: Fong
authors.forename: Sally R
authors.initials: SR
authors.lastname: James
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Eggo
authors.forename: Kristien
authors.initials: K
authors.lastname: Boelaert
authors.forename: Jayne A
authors.initials: JA
authors.lastname: Franklyn
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McCabe
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D022461:Caveolins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D017353:Gene Deletion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007454:Iodides / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D000090063:Proto-Oncogene Mas; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*; D060149:Tetraspanin 30; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000099209:Sodium-Iodide Symporters
chemical_list: D015703:Antigens, CD; D022461:Caveolins; D047908:Intracellular Signaling Peptides and Proteins; D007454:Iodides; D008565:Membrane Proteins; D010980:Platelet Membrane Glycoproteins; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; D027981:Symporters; D060149:Tetraspanin 30; D000099209:Sodium-Iodide Symporters; C554586:CD63 protein, human; C554588:Cd63 protein, rat; C000715470:MAS1 protein, human; C112633:PTTG1IP protein, human
references.citation: J Cell Sci. 2004 Feb 15;117(Pt 5):677-87
references.pmid: 14734652
references.citation: BMC Cancer. 2007 Jul 25;7:137
references.pmid: 17651485
references.citation: J Clin Endocrinol Metab. 2003 Oct;88(10):4977-83
references.pmid: 14557483
references.citation: J Clin Endocrinol Metab. 1998 Nov;83(11):4102-6
references.pmid: 9814499
references.citation: J Clin Invest. 1998 Apr 1;101(7):1296-300
references.pmid: 9525971
references.citation: Endocrinology. 1997 Aug;138(8):3555-8
references.pmid: 9231811
references.citation: Oncogene. 2007 Jun 28;26(30):4344-56
references.pmid: 17297475
references.citation: Mol Endocrinol. 2005 Nov;19(11):2847-58
references.pmid: 15976004
references.citation: J Endocrinol. 1999 Dec;163(3):495-504
references.pmid: 10588823
references.citation: Thyroid. 2000 Mar;10(3):211-7
references.pmid: 10779135
references.citation: J Clin Endocrinol Metab. 2005 Nov;90(11):6131-40
references.pmid: 16105966
references.citation: Biochem Biophys Res Commun. 1996 Sep 13;226(2):339-45
references.pmid: 8806637
references.citation: Endocrinology. 1997 Jun;138(6):2227-32
references.pmid: 9165005
references.citation: J Clin Endocrinol Metab. 1999 Aug;84(8):2957-62
references.pmid: 10443704
references.citation: Cancer Lett. 2003 Oct 8;200(1):85-91
references.pmid: 14550956
references.citation: J Clin Endocrinol Metab. 2001 Apr;86(4):1447-63
references.pmid: 11297567
references.citation: Mod Pathol. 2001 Apr;14(4):289-96
references.pmid: 11301345
references.citation: J Clin Endocrinol Metab. 2001 Oct;86(10):5025-32
references.pmid: 11600580
references.citation: J Clin Endocrinol Metab. 2006 Apr;91(4):1404-9
references.pmid: 16418208
references.citation: Endocrinology. 1998 Oct;139(10):4416-9
references.pmid: 9751526
references.citation: EMBO J. 2000 Sep 1;19(17):4759-73
references.pmid: 10970867
references.citation: J Biol Chem. 2001 Jun 15;276(24):21458-63
references.pmid: 11290744
references.citation: Endocr Relat Cancer. 2006 Sep;13(3):797-826
references.pmid: 16954431
references.citation: J Clin Endocrinol Metab. 2003 May;88(5):2341-7
references.pmid: 12727994
references.citation: Endocrinology. 2009 Apr;150(4):1961-9
references.pmid: 19022891
references.citation: Eur J Endocrinol. 2000 Apr;142(4):340-6
references.pmid: 10754474
references.citation: J Clin Endocrinol Metab. 1999 Sep;84(9):3228-34
references.pmid: 10487692
references.citation: Endocrinology. 2003 Jan;144(1):247-52
references.pmid: 12488351
references.citation: J Clin Endocrinol Metab. 2003 Apr;88(4):1880-8
references.pmid: 12679487
references.citation: Biochem Biophys Res Commun. 1997 Nov 26;240(3):832-8
references.pmid: 9398654
references.citation: Endocr Rev. 2003 Feb;24(1):48-77
references.pmid: 12588808
references.citation: Thyroid. 1999 Apr;9(4):405-9
references.pmid: 10319949
references.citation: J Biol Chem. 2000 Jun 23;275(25):19422-7
references.pmid: 10781616
references.citation: Proc Natl Acad Sci U S A. 1980 Jun;77(6):3455-9
references.pmid: 6106191
references.citation: J Clin Endocrinol Metab. 2001 Jun;86(6):2697-700
references.pmid: 11397873
references.citation: Eur J Endocrinol. 2003 May;148(5):579-86
references.pmid: 12720543
references.citation: Traffic. 2007 Feb;8(2):89-96
references.pmid: 17181773
references.citation: Thyroid. 2007 Mar;17(3):203-11
references.pmid: 17381352
references.citation: Lancet. 2003 Mar 8;361(9360):796-7
references.pmid: 12642042
references.citation: Am J Pathol. 2004 Jul;165(1):25-34
references.pmid: 15215159
references.citation: J Biol Chem. 2007 Dec 21;282(51):36820-8
references.pmid: 17913707
references.citation: J Clin Endocrinol Metab. 1998 Jul;83(7):2493-6
references.pmid: 9661633
references.citation: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3789-93
references.pmid: 8170988
references.citation: Thyroid. 1999 Aug;9(8):821-30
references.pmid: 10482376
references.citation: Genomics. 1998 Apr 1;49(1):133-6
references.pmid: 9570958
references.citation: J Clin Endocrinol Metab. 2005 Jul;90(7):4341-9
references.pmid: 15886233