RRC ID 28470
Author Shimamura M, Nakahara M, Orim F, Kurashige T, Mitsutake N, Nakashima M, Kondo S, Yamada M, Taguchi R, Kimura S, Nagayama Y.
Title Postnatal expression of BRAFV600E does not induce thyroid cancer in mouse models of thyroid papillary carcinoma.
Journal Endocrinology
Abstract The mutant BRAF (BRAF(V600E)) is the most common genetic alteration in papillary thyroid carcinomas (PTCs). The oncogenicity of this mutation has been shown by some genetically engineered mouse models. However, in these mice, BRAF(V600E) is expressed in all the thyroid cells from the fetal periods, and suppresses thyroid function, thereby leading to TSH elevation, which by itself promotes thyroid tumorigenesis. To overcome these problems, we exploited 2 different approaches, both of which allowed temporally and spatially restricted expression of BRAF(V600E) in the thyroid glands. First, we generated conditional transgenic mice harboring the loxP-neo(R)-loxP-BRAF(V600E)-internal ribosome entry site-green fluorescent protein sequence [Tg(LNL-BRAF(V600E))]. The double transgenic mice (LNL-BRAF(V600E);TPO-Cre) were derived from a high expressor line of Tg(LNL-BRAF(V600E)) mice and TPO-Cre mice; the latter expresses Cre DNA recombinase under the control of thyroid-specific thyroid peroxidase (TPO) promoter and developed PTC-like lesions in early life under normal serum TSH levels due to mosaic recombination. In contrast, injection of adenovirus expressing Cre under the control of another thyroid-specific thyroglobulin (Tg) promoter (Ad-TgP-Cre) into the thyroids of LNL-BRAF(V600E) mice did not induce tumor formation despite detection of BRAF(V600E) and pERK in a small fraction of thyroid cells. Second, postnatal expression of BRAF(V600E) in a small number of thyroid cells was also achieved by injecting the lentivirus expressing loxP-green fluorescent protein-loxP-BRAF(V600E) into the thyroids of TPO-Cre mice; however, no tumor development was again observed. These results suggest that BRAF(V600E) does not appear to induce PTC-like lesions when expressed in a fraction of thyroid cells postnatally under normal TSH concentrations.
Volume 154(11)
Pages 4423-30
Published 2013-11-1
DOI 10.1210/en.2013-1174
PII en.2013-1174
PMID 23970782
MeSH Animals Carcinoma, Papillary / metabolism* Gene Expression Regulation, Developmental / physiology* Gene Expression Regulation, Neoplastic / physiology* Genes, Transgenic, Suicide Iodide Peroxidase Mice Mutation Proto-Oncogene Proteins B-raf / genetics Proto-Oncogene Proteins B-raf / metabolism* Thyroid Neoplasms / metabolism* Thyroxine / metabolism
IF 3.934
Times Cited 17
DNA material pCALNL5 (RDB01862) Ad-TgP-Cre (RDB19710)