ArticleThe Journal of clinical endocrinology and metabolism2012
PTEN lipid phosphatase activity and proper subcellular localization are necessary and sufficient for down-regulating AKT phosphorylation in the nucleus in Cowden syndrome.
Article in The Journal of clinical endocrinology and metabolism, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- Germline PTEN genotype-dependent phenotypic divergence during the early neural developmental process of forebrain organoids.Molecular psychiatry · 2024Article
- PTEN modulates gene transcription by redistributing genome-wide RNA polymerase II occupancy.Human molecular genetics · 2019Article
- PTEN interacts with RNA polymerase II to dephosphorylate polymerase II C-terminal domain.Oncotarget · 2019Article
- Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel.Human mutation · 2018Article
- Differential regulation of AKT1 contributes to survival and proliferation in hepatocellular carcinoma cells by mediating Notch1 expression.Oncology letters · 2018Article
- Fortunellin-Induced Modulation of Phosphatase and Tensin Homolog by MicroRNA-374a Decreases Inflammation and Maintains Intestinal Barrier Function in Colitis.Frontiers in immunology · 2018Article
- Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells.Human molecular genetics · 2017Article
- Phosphatidylinositolphosphate phosphatase activities and cancer.Journal of lipid research · 2016Review
- HCV infection-associated hepatocellular carcinoma in humanized mice.Infectious agents and cancer · 2015Article
- PI3K/AKT pathway mediates induction of IL-1RA by TSH in fibrocytes: modulation by PTEN.The Journal of clinical endocrinology and metabolism · 2014Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
contextGermline 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.
objectiveThe 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.
designIn 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.
resultsLoss 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.
conclusionsPTEN is necessary and sufficient for inhibiting AKT activation in the nucleus through its intact lipid phosphatase activity and proper subcellular localization.
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