Forskolin, 8-Br-3',5'-cyclic adenosine 5'-monophosphate, and catalytic protein kinase A expression in the nucleus increase radioiodide uptake and sodium/iodide symporter protein levels in RET/PTC1-expressing cells.
RET/PTC1, a thyroid-specific oncogene, has been reported to down-regulate sodium/iodide symporter (NIS) expression and function in vitro and in vivo. Recently, RET/PTC1 has been shown to interfere with TSH signaling at multiple levels in thyroid cells. The objective of this study was to investigate whether RET/PTC1-mediated NIS reduction can be rescued by activating cAMP-protein kinase A (PKA) pathways. We showed that both forskolin and 8-Br-cAMP increase radioiodide uptake and NIS protein in RET/PTC1-expressing cells to the same extent as the parental PC Cl 3 cells. We found that RET/PTC1 decreases nuclear localization of catalytic PKA, and forskolin treatment was able to counteract this RET/PTC1 effect. Furthermore, transient expression of catalytic PKA in the nucleus increased radioiodide uptake and NIS protein in RET/PTC1-expressing cells. Taken together, these studies suggest that RET/PTC1 down-regulates NIS expression by interrupting TSH/cAMP signaling, and this RET/PTC1 effect can be reversed by activating cAMP-PKA pathways.
Venkateswaran
Anjli
A
The Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio 43210, USA.
Marsee
Derek K
DK
Green
Steven H
SH
Jhiang
Sissy M
SM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects / Q000235:genetics; D000099209:Sodium-Iodide Symporters
D015124:8-Bromo Cyclic Adenosine Monophosphate; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D049452:Green Fluorescent Proteins; D007457:Iodine Radioisotopes; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C093573:ret-PTC fusion oncoproteins, human