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J Clin Endocrinol Metab. 2012 Nov;97(11):E2179-87. doi: 10.1210/jc.2012-1991. Epub 2012 Sep 7.

PTEN lipid phosphatase activity and proper subcellular localization are necessary and sufficient for down-regulating AKT phosphorylation in the nucleus in Cowden syndrome.

Author information

1
Cleveland Clinic, 9500 Euclid Avenue, NE50, Cleveland, Ohio 44195, USA.

Abstract

CONTEXT:

Germline mutations in PTEN are associated with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) hamartoma tumor syndrome including Cowden syndrome (CS) and Cowden-like syndrome (CSL) that predisposes to high risks of benign and malignant tumors of thyroid and breast.

OBJECTIVE:

The objective of the study was to analyze the subcellular pattern of phosphorylated (P)-AKT expression in nonmedullary thyroid cancers from PTEN hamartoma tumor syndrome patients and to investigate whether the lack of PTEN in the nucleus and/or lack of proper PTEN function in the nucleus affect(s) nuclear AKT activity in CS patients.

DESIGN:

In all, 664 patients with CS/CSL were screened for PTEN germline mutations and nonmedullary thyroid cancers. Twenty-two patients who have both pathogenic PTEN germline mutations and nonmedullary thyroid cancers were selected. Thyroid samples from these patients were stained for PTEN and P-AKT. In our in vitro study, PTEN was knocked down or overexpressed in both thyroid cancer cells and breast cancer cells, and nuclear P-AKT was compared with the control.

RESULTS:

Loss of PTEN protein was found in thyroid adenomas and carcinomas from all 22 (100%) PTEN(Mut+) CS/CSL patients. AKT activation was identified in 17 of 22 (77.3%) thyroid adenoma/carcinoma specimens, and most patients (63.7%) have activated nuclear AKT. Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT, whereas expression of wild-type PTEN, but not phosphatase-dead mutants (C124S or G129E), markedly reduced nuclear P-AKT in PTEN null cells. We also showed that in breast cancer but not thyroid cancer cells, PTEN suppresses nuclear P-AKT mainly through decreasing P-AKT nuclear translocation by reducing the PIP3/P-AKT reservoir in the cytoplasm. In thyroid cancer cells, PTEN suppresses phosphorylation of AKT already resident in the nucleus.

CONCLUSIONS:

PTEN is necessary and sufficient for inhibiting AKT activation in the nucleus through its intact lipid phosphatase activity and proper subcellular localization.

PMID:
22962422
PMCID:
PMC3485596
DOI:
10.1210/jc.2012-1991
[Indexed for MEDLINE]
Free PMC Article

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