PTEN: The down side of PI 3-kinase signalling

Leslie, Nicholas R.; Downes, C P

doi:10.1016/s0898-6568(01)00234-0

Cited by 390 publications

(293 citation statements)

References 105 publications

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“…9,39,40 Its role as a tumour suppressor was first documented when ectopically expressed wild-type PTEN arrested cell cycling in glioblastoma cells harbouring mutated PTEN. 41,42 Since then, mutations in PTEN have been described in several human malignancies arising from multiple tissue types, including epithelial (endometrial, prostate, lung, breast, gastric), neuronal (glioblastoma), hematogenous (myeloma) and neuro-endocrine (thyroid, melanomas) tumours.…”

Section: Discussionmentioning

confidence: 99%

“…43 It is certain that reduced expression of PTEN results in unopposed PKB activation, which can effect either cell cycle arrest (probably mediated through up-regulation of p27 KIP1 ), 44 or increased survival (through multiple anti-apoptotic pathways). 40,45 Immunohistochemical analysis of PTEN expression is a powerful tool by which one can evaluate its role in human malignancies. This has been conducted for several human cancers such as prostate, 46 thyroid, 47 endometrial, 48 melanoma, 49 ovarian 50 and gastric 51 carcinomas, to name a few.…”

Section: Discussionmentioning

confidence: 99%

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Dysregulated PTEN‐PKB and negative receptor status in human breast cancer

Shi

Zhang

Pintilie

et al. 2003

Intl Journal of Cancer

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Recent studies demonstrate that abnormalities in PTEN may be one of the most frequent genetic events observed in human cancers. PTEN dysfunction leads to tumorigenesis through unopposed survival signals mediated via activated protein kinase B (PKB), which may also be associated with hormone-independence. We therefore investigated the relationship between PTEN-PKB and receptor status in human breast cancer. Several molecular variables, including immunohistochemical staining for PTEN, PKB (phosphorylated on ser473), p53 and p21 were evaluated. The p53 gene was sequenced from exons 2-11. Seventy-eight participants in a randomised breast cancer trial served as the cohort for our study. Twenty-eight of 77 (36%) patients' tumours demonstrated absent or reduced PTEN expression; 17 of 78 (22%) tumours over-expressed P-PKB. A significant inverse relationship was observed between reduced PTEN and increased P-PKB expression. Reduced PTEN also correlated with reduced ER or PR expression. None of the molecular variables correlated with survival. ER and PR negative tumours, however, experienced a significantly inferior disease-free survival than other ER/PR status tumours. Immunohistochemical analyses of ER expression in mammary carcinomas arising in PTEN heterozygous knockout mice did not demonstrate a reduction in ER immunoreactivity, in comparison to wildtype mice. Our data demonstrate that the PTEN-PKB pathway is abnormal in approximately 1 ⁄3 of lymph node negative breast cancer. Dysregulated PTEN-PKB was also associated with reduced ER/PR expression, but this does not appear to be a simple direct causal relationship. These observations support the contention that dysregulation in PTEN-PKB contributes to disease progression and hormone resistance of human breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dysregulated PTEN‐PKB and negative receptor status in human breast cancer

Shi

Zhang

Pintilie

et al. 2003

Intl Journal of Cancer

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“…Therefore, although both PTEN and SHIP dephosphorylate PI-3,4,5-P 3 , PTEN apparently functions as the primary negative regulator of the PI3-K-Akt pathway. [13][14][15][16] On the other hand, phosphorylation of Akt can also be controlled by serine/threonine protein phosphatases. [17][18][19] PP1 and PP2A are two major classes of serine/threonine protein phosphatases that are involved in many different cellular processes, including glycogen metabolism, cell cycle regulation, protein synthesis and intracellular transport, RNA splicing, and signal transduction.…”

Section: Mechanisms Of Akt Regulationmentioning

confidence: 99%

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Ittmann

Ayala

et al. 2005

Prostate Cancer Prostatic Dis

112

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The PI3-K-Akt pathway plays a central role in the development and progression of prostate cancer and other malignancies. We review original studies and summarize relevant sections of previous reviews concerning the relationships between abnormalities in the PI3-K-Akt pathway and prostate cancer progression. We discuss laboratory and clinical data that indicate gene perturbation and dysregulation of PI3-K-Akt pathway is common in prostate cancer and other malignancies. We further discuss the critical role of the PI3-K-Akt pathway in the oncogenic signaling network and provide examples that establish the PI3-K-Akt pathway as a focal point for the future development of informative biomarkers and effective therapies for prostate cancer.

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“…Akt signaling is restrained by PTEN (phosphatase and tensin homolog deleted on chromosome 10), a phosphatase and tumor suppressor that dephosporylates PIP 3 to PIP 2 (Leslie and Downes, 2002). By reducing the levels of PIP 3, PTEN inhibits the recruitment of Akt to the plasma membrane and prevents its activation.…”

Section: Introductionmentioning

confidence: 99%

Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor

2007

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Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes are overexpressed during inflammation and multistage tumor progression in many neoplastic disorders including lung, breast and pancreatic cancers. Here we report that the tumor suppressor phosphatase and tensin homolog (PTEN) is oxidized and inactivated during arachidonic acid (AA) metabolism in pancreatic cancer cell lines expressing COX-2 or 5-LOX. Oxidation of PTEN decreases its phosphatase activity, favoring increased phosphatidylinositol 3,4,5-triphosphate production, activation of Akt and phosphorylation of downstream Akt targets including GSK-3b and S6K. These effects are recapitulated with pancreatic phospholipase A 2 , which hydrolyses the release of membrane-bound AA. Interference with PTEN's physiological antagonism of signals from growth factors, insulin and oncogenes may confer risk for hypertrophic or neoplastic diseases associated with chronic inflammation or unwarranted oxidative metabolism of essential fatty acids.

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PTEN: The down side of PI 3-kinase signalling

Cited by 390 publications

References 105 publications

Dysregulated PTEN‐PKB and negative receptor status in human breast cancer

Dysregulated PTEN‐PKB and negative receptor status in human breast cancer

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor

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