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PMID:10918569

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Citation

Bruni, P, Boccia, A, Baldassarre, G, Trapasso, F, Santoro, M, Chiappetta, G, Fusco, A and Viglietto, G (2000) PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated by p27kip1. Oncogene 19:3146-55

Abstract

The dual-specificity phosphatase PTEN/MMAC1/TEP1 has recently been identified as the tumor suppressor gene most frequently mutated and/or deleted in human tumors. Germline mutations of PTEN give rise to Cowden Disease (CD), an autosomal dominantly-inherited cancer syndrome which predisposes to increased risk of developing breast and thyroid tumors. However, PTEN mutations have rarely been detected in sporadic thyroid carcinomas. In this study, we confirm that PTEN mutations in sporadic thyroid cancer are infrequent as we found one point mutation and one heterozygous deletion of PTEN gene in 26 tumors and eight cell lines screened. However, we report that PTEN expression is reduced both at the mRNA and at the protein level - in five out of eight tumor-derived cell lines and in 24 out of 61 primary tumors. In most cases, decreased PTEN expression is correlated with increased phosphorylation of the PTEN-regulated protein kinase Akt/PKB. Moreover, we demonstrate that PTEN may act as a suppressor of thyroid cancerogenesis as the constitutive re-expression of PTEN into two different thyroid tumor cell lines markedly inhibits cell growth. PTEN-dependent inhibition of BrdU incorporation is accompanied by enhanced expression of the cyclin-dependent kinase inhibitor p27kip1 and can be overcome by simultaneous co-transfection of an excess p27kip1 antisense plasmid. Accordingly, in a subset of thyroid primary carcinomas and tumor-derived cell lines, a striking correlation between PTEN expression and the level of p27kip1 protein was observed. In conclusion, our findings demonstrate that inactivation of PTEN may play a role in the development of sporadic thyroid carcinomas and that one key target of PTEN suppressor activity is represented by the cyclin-dependent kinase inhibitor p27kip1.

Links

PubMed Online version:10.1038/sj.onc.1203633

Keywords

Blotting, Northern; Blotting, Western; Carcinoma/genetics; Carcinoma/metabolism; Cell Cycle Proteins; Cell Division; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases/antagonists & inhibitors; Enzyme Inhibitors; Gene Deletion; Gene Expression; Genes, Tumor Suppressor; Humans; Microtubule-Associated Proteins/metabolism; Mutagenesis; PTEN Phosphohydrolase; Phosphoric Monoester Hydrolases/biosynthesis; Phosphoric Monoester Hydrolases/genetics; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; S Phase; Thyroid Neoplasms/genetics; Thyroid Neoplasms/metabolism; Tumor Cells, Cultured; Tumor Suppressor Proteins; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CDN1B

enables

GO:0004861: cyclin-dependent protein serine/threonine kinase inhibitor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PTEN

involved_in

GO:0033137: negative regulation of peptidyl-serine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTEN

involved_in

GO:1902807: negative regulation of cell cycle G1/S phase transition

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTEN

involved_in

GO:0008283: cell population proliferation

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTEN

involved_in

GO:0000079: regulation of cyclin-dependent protein serine/threonine kinase activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete


See also

References

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