Reversible Inactivation of the Tumor Suppressor PTEN by H2O2

Lee, Seung-Rock; Yang, Kap‐Seok; Kwon, Jaeyul; Lee, Chung-Hee; Jeong, Woojin; Rhee, Sue Goo

doi:10.1074/jbc.m111899200

Cited by 926 publications

(782 citation statements)

References 53 publications

Supporting

Mentioning

749

Contrasting

Unclassified

Order By: Relevance

“…7). Our findings support an earlier suggestion that PTEN is regulated by ROS (49). As PTEN phosphorylation on Ser380/Thr 382/383 is thought to inhibit its phosphatase activity (50), our findings suggest that fluprostenol may act to limit the inhibitory influence of PTEN on PI3K signaling and its downstream effector Akt.…”

Section: Discussionsupporting

confidence: 91%

PGF2α-associated vascular smooth muscle hypertrophy is ROS dependent and involves the activation of mTOR, p70S6k, and PTEN

Rice

Uddemarri

Desai

et al. 2008

Prostaglandins & Other Lipid Mediators

View full text Add to dashboard Cite

Prostaglandin F 2α (PGF2α) increases reactive oxygen species (ROS) and induces vascular smooth muscle cell (VSMC) hypertrophy by largely unknown mechanism(s). To investigate the signaling events governing PGF2α -induced VSMC hypertrophy we examined the ability of the PGF2α analog, fluprostenol to elicit phosphorylation of Akt, the mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70 S6k ), glycogen synthase kinase-3β (GSK-3β), phosphatase and tensin homolog (PTEN), extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) in growth arrested A7r5 VSMC. Fluprostenol-induced hypertrophy was associated with increased ROS, mTOR translocation from the nucleus to the cytoplasm, along with Akt, mTOR, GSK-3β, PTEN and ERK1/2 but not JNK phosphorylation. Whereas inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002 blocked fluprostenol-induced changes in total protein content, pretreatment with rapamycin or with the ERK1/2-MAPK inhibitor UO126 did not. Taken together, these findings suggest that fluprostenol-induced changes in A7R5 hypertrophy involve mTOR translocation and occur through PI3K-dependent mechanisms.

show abstract

Section: Discussionsupporting

confidence: 91%

PGF2α-associated vascular smooth muscle hypertrophy is ROS dependent and involves the activation of mTOR, p70S6k, and PTEN

Rice

Uddemarri

Desai

et al. 2008

Prostaglandins & Other Lipid Mediators

View full text Add to dashboard Cite

show abstract

“…By reducing the levels of PIP 3, PTEN inhibits the recruitment of Akt to the plasma membrane and prevents its activation. PTEN function is regulated by post-translational modification, cellular localization and redox modulation at the active-site cysteine (Lee et al, 2002;Yu et al, 2005;Gericke et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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

2007

View full text Add to dashboard Cite

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.

show abstract

“…Ubiquitination at K 289 and K 13 is regulated by the E3 ubiquitin ligases NEDD4-1 15,16 and WWP2 17 ; the polyubiquitinated PTEN protein undergoes rapid degradation, whereas the monoubiquitinated form manifests the increased translocation to the nucleus. Oxidation of disulphide linkage of catalytic C 124 with C 71 mediated by reactive oxygen species also negatively regulates PTEN catalytic activity 18 . S-nitrosylation at the major site C 87 (minor sites including C 71 and C 124 ) by reactive nitrogen species inactivates its lipid phosphatase activity and mediates PTEN degradation via ubiquitination 19 .…”

mentioning

confidence: 99%

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

et al. 2012

View full text Add to dashboard Cite

The membrane association of the tumour suppressor phosphatase and tensin homologue (PTEN) is required to oppose the phosphatidylinositol-3-kinase / AKT pathway by dephosphorylation of phosphatidylinositol-3,4,5-triphosphate (PIP3). How cytosolic PTEN interacts with its main substrate, PIP3, localized at the inner face of plasma membrane remains unclear. Here we show that PTEN is covalently modifi ed by SUMO1 at both K 266 and K 254 sites in the C2 domain of PTEN. SUMO1 modifi cation at K 266 located in the CBR3 loop, which has a central role in PTEN membrane association, mainly facilitates cooperative binding of PTEN to the plasma membrane by electrostatic interactions. This results in the downregulation of the phosphatidylinositol-3 kinase / AKT pathway and consequently, suppression of anchorageindependent cell proliferation and tumour growth in vivo . Our data demonstrate a molecular mechanism whereby SUMO1 modifi cation is required for PTEN tumour suppressor function by controlling PTEN membrane association and regulation of the phosphatidylinositol-3 kinase / AKT pathway.

show abstract

Reversible Inactivation of the Tumor Suppressor PTEN by H2O2

Cited by 926 publications

References 53 publications

PGF2α-associated vascular smooth muscle hypertrophy is ROS dependent and involves the activation of mTOR, p70S6k, and PTEN

PGF2α-associated vascular smooth muscle hypertrophy is ROS dependent and involves the activation of mTOR, p70S6k, and PTEN

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

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

Contact Info

Product

Resources

About