A novel mechanism of sodium iodide symporter repression in differentiated thyroid cancer.
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.
Smith
Vicki E
VE
School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham B15 2TH, UK.
Read
Martin L
ML
Turnell
Andrew S
AS
Watkins
Rachel J
RJ
Watkinson
John C
JC
Lewy
Greg D
GD
Fong
Jim C W
JC
James
Sally R
SR
Eggo
Margaret C
MC
Boelaert
Kristien
K
Franklyn
Jayne A
JA
McCabe
Christopher J
CJ
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
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
J Cell Sci. 2004 Feb 15;117(Pt 5):677-87
14734652
BMC Cancer. 2007 Jul 25;7:137
17651485
J Clin Endocrinol Metab. 2003 Oct;88(10):4977-83
14557483
J Clin Endocrinol Metab. 1998 Nov;83(11):4102-6
9814499
J Clin Invest. 1998 Apr 1;101(7):1296-300
9525971
Endocrinology. 1997 Aug;138(8):3555-8
9231811
Oncogene. 2007 Jun 28;26(30):4344-56
17297475
Mol Endocrinol. 2005 Nov;19(11):2847-58
15976004
J Endocrinol. 1999 Dec;163(3):495-504
10588823
Thyroid. 2000 Mar;10(3):211-7
10779135
J Clin Endocrinol Metab. 2005 Nov;90(11):6131-40
16105966
Biochem Biophys Res Commun. 1996 Sep 13;226(2):339-45
8806637
Endocrinology. 1997 Jun;138(6):2227-32
9165005
J Clin Endocrinol Metab. 1999 Aug;84(8):2957-62
10443704
Cancer Lett. 2003 Oct 8;200(1):85-91
14550956
J Clin Endocrinol Metab. 2001 Apr;86(4):1447-63
11297567
Mod Pathol. 2001 Apr;14(4):289-96
11301345
J Clin Endocrinol Metab. 2001 Oct;86(10):5025-32
11600580
J Clin Endocrinol Metab. 2006 Apr;91(4):1404-9
16418208
Endocrinology. 1998 Oct;139(10):4416-9
9751526
EMBO J. 2000 Sep 1;19(17):4759-73
10970867
J Biol Chem. 2001 Jun 15;276(24):21458-63
11290744
Endocr Relat Cancer. 2006 Sep;13(3):797-826
16954431
J Clin Endocrinol Metab. 2003 May;88(5):2341-7
12727994
Endocrinology. 2009 Apr;150(4):1961-9
19022891
Eur J Endocrinol. 2000 Apr;142(4):340-6
10754474
J Clin Endocrinol Metab. 1999 Sep;84(9):3228-34
10487692
Endocrinology. 2003 Jan;144(1):247-52
12488351
J Clin Endocrinol Metab. 2003 Apr;88(4):1880-8
12679487
Biochem Biophys Res Commun. 1997 Nov 26;240(3):832-8
9398654
Endocr Rev. 2003 Feb;24(1):48-77
12588808
Thyroid. 1999 Apr;9(4):405-9
10319949
J Biol Chem. 2000 Jun 23;275(25):19422-7
10781616
Proc Natl Acad Sci U S A. 1980 Jun;77(6):3455-9
6106191
J Clin Endocrinol Metab. 2001 Jun;86(6):2697-700
11397873
Eur J Endocrinol. 2003 May;148(5):579-86
12720543
Traffic. 2007 Feb;8(2):89-96
17181773
Thyroid. 2007 Mar;17(3):203-11
17381352
Lancet. 2003 Mar 8;361(9360):796-7
12642042
Am J Pathol. 2004 Jul;165(1):25-34
15215159
J Biol Chem. 2007 Dec 21;282(51):36820-8
17913707
J Clin Endocrinol Metab. 1998 Jul;83(7):2493-6
9661633
Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3789-93
8170988
Thyroid. 1999 Aug;9(8):821-30
10482376
Genomics. 1998 Apr 1;49(1):133-6
9570958
J Clin Endocrinol Metab. 2005 Jul;90(7):4341-9
15886233