Creation and characterization of a doxycycline-inducible mouse model of thyroid-targeted RET/PTC1 oncogene and luciferase reporter gene coexpression.
BACKGROUND
RET/PTC1 chromosomal rearrangement is associated with papillary thyroid carcinoma formation in children exposed to ionizing radiation. We previously created a transgenic mouse model with thyroid-targeted constitutive RET/PTC1 expression and demonstrated papillary thyroid carcinoma formation.


OBJECTIVE
In this study, we aimed to create a doxycycline-inducible mouse model of thyroid RET/PTC1 and luciferase reporter gene coexpression to allow for noninvasive monitoring of transgene expression in mice of various ages and timepoints after induction.


METHODS
Transgenic mice carrying the rtTA gene driven by the thyroglobulin promoter were generated, and crossed with responder mice carrying RET/PTC1 and firefly luciferase genes under control of a bidirectional tetracycline response element.


RESULTS
Most bitransgenic mice had thyroid-targeted, doxycycline-independent transgene expression. Only one line had thyroid-targeted, doxycycline-regulated RET/PTC1 and luciferase coexpression, in which doxycycline induction of RET/PTC1 led to Erk phosphorylation and reduced expression of the sodium/iodide symporter (NIS). However, thyroid lesions were not found in any bitransgenic mice examined.


CONCLUSIONS
We found that acute RET/PTC1 expression can activate the MEK/Erk pathway and downregulate NIS expression in the mouse thyroid gland. However, a higher level of RET/PTC1 is likely necessary for tumor formation. Thyroid luciferase induction was detectable noninvasively using IVIS in vivo imaging.
Knostman
Katherine A B
KA
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.
Venkateswaran
Anjli
A
Zimmerman
Bevin
B
Capen
Charles C
CC
Jhiang
Sissy M
SM
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002291:Carcinoma, Papillary / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics*; D008156:Luciferases / Q000235:genetics* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology; D000099209:Sodium-Iodide Symporters
D000900:Anti-Bacterial Agents; D004318:Doxycycline; D048049:Extracellular Signal-Regulated MAP Kinases; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D051096:Proto-Oncogene Proteins c-ret; D011956:Receptors, Cell Surface; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C000606240:Ptch1 protein, mouse; C494999:Ret protein, mouse