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Loss of p27 Expression Through RAS->BRAF->MAP Kinase-Dependent Pathway in Human Thyroid Carcinomas
- Source :
- Cell Cycle. 6:2817-2825
- Publication Year :
- 2007
- Publisher :
- Informa UK Limited, 2007.
-
Abstract
- In the present study, we report that the RAS/BRAF/MAP kinase cascade plays a crucial role in the regulation of the Skp2/p27 pathway in thyroid cancer cells and that this is critical for cell proliferation. In vitro studies with cellular models of human thyroid carcinoma cells demonstrated that the adoptive expression of oncogenic RET/PTC1, Ha-RASV12 or BRAFV600E enhances Skp2 and reduces p27 protein expression in a MAP kinase-dependent manner; that RAS/BRAF/MAP kinase-dependent control of p27 expression in thyroid cancer cells occurs by regulating the stability of Skp2 and p27 protein; and that antisense oligonucleotides to p27 suppress growth arrest induced by MEK inhibitors. Finally, analysis of human thyroid carcinomas indicated that MAP kinase-positive thyroid tumors-as detected by immunostaining for p-ERK - presented high p27 degradative activity and low levels of p27 protein (n = 30; p < 0.05). In summary, our results indicate that constitutive signalling of the MAP kinase cascade contributes to the development of thyroid cancer promoted by activated RAS and BRAF oncogenes and that this occurs, at least in part, by compromising the inhibitory function of p27.
- Subjects :
- Proto-Oncogene Proteins B-raf
endocrine system diseases
MAP Kinase Signaling System
thyroid
Cell Line, Tumor
medicine
SKP2
Humans
Thyroid Neoplasms
Molecular Biology
Thyroid cancer
Thyroid hormone receptor
biology
Oncogene
Cell growth
Thyroid
Cell Biology
medicine.disease
Gene Expression Regulation, Neoplastic
Genes, ras
medicine.anatomical_structure
Mitogen-activated protein kinase
biology.protein
Cancer research
cell cycle
Mitogen-Activated Protein Kinases
ra
Cyclin-Dependent Kinase Inhibitor p27
braf
Developmental Biology
Subjects
Details
- ISSN :
- 15514005 and 15384101
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Cell Cycle
- Accession number :
- edsair.doi.dedup.....a37bb47f04e515ab65f97fcec7ba1dcb