Protein phosphatase 2A is the main phosphatase involved in the regulation of protein kinase B in rat adipocytes

Resjö, Svante; Göransson, Olga; Härndahl, Linda; Zołnierowicz, Stanisław; Manganiello, Vincent C.; Degerman, Eva

doi:10.1016/s0898-6568(01)00238-8

Cited by 127 publications

(111 citation statements)

References 54 publications

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“…Our in vitro and in vivo data indicate that FAS inhibition indeed results in decreased AKT activity. However, other possibilities, including inhibition of PI3K or activation of PTEN or protein phosphatase-2A (Resjo et al, 2002) by lipid intermediates that accumulate following FAS inhibition, may also contribute to the decreased levels of phospho-AKT. Our in vivo studies of the effect of C75 on SKOV3 tumor growth in a murine xenograft model are consistent with results obtained with breast cancer and mesothelioma xenograft models Gabrielson et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells

et al. 2005

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Activation of AKT and overexpression of fatty acid synthase (FAS) are frequently observed in human ovarian cancer. To explore a possible connection between AKT and FAS, immunohistochemical analyses were conducted on an ovarian cancer tissue microarray, which revealed a significant correlation between phosphorylated AKT (phospho-AKT) and expression of FAS. To investigate the relationship between phospho-AKT and FAS in vitro, a variety of experiments employing a specific phosphatidylinositol 3-OH kinase (PI3K) inhibitor (LY294002), inducible PTEN expression in PTEN-null cells, or AKT1 siRNA demonstrated that phosphatidylinositol-3 kinase (PI3K)/AKT signaling modulates FAS expression. In contrast, inhibition of FAS activity by the drug C75 resulted in downregulation of phospho-AKT and increased cell death. To explore the functional relationship between phospho-AKT and FAS, we used SKOV3, C200, and OVCAR10 ovarian carcinoma cells, which have constitutively active AKT, and OVCAR5 cells, which have very low basal phospho-AKT levels. Treatment with LY294002 abolished AKT activity and potentiated apoptosis induced by FAS inhibitors cerulenin or C75 only in cells with constitutively active AKT, suggesting that constitutive activation of AKT protects against FAS inhibitor-induced cell death. Furthermore, inhibition of FAS activity by cerulenin or C75 resulted in downregulation of phospho-AKT, which preceded the induction of apoptosis. To investigate the relationship between phospho-AKT and FAS in vivo, severe combined immunodeficient mice injected intraperitoneally with SKOV3 cells were treated with C75. Growth of SKOV3 xenografts was markedly inhibited by C75. Analysis of the levels of phospho-AKT and FAS in C75-treated tumors revealed concordant downregulation of phospho-AKT and FAS. Collectively, our findings are consistent with a working model in which AKT activation regulates FAS expression, at least in part, whereas FAS activity modulates AKT activation.

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Section: Discussionmentioning

confidence: 99%

Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells

et al. 2005

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“…Okadaic acid is an inhibitor of the protein phosphatase 2A and leads to an accumulation of pAkt and activation of the Akt pathway. 31,32 We exposed cells for 48 hr time to okadaic acid, and examined the induction of NOS2 and COX2 by Western blot analysis (Fig. 2c).…”

Section: Treatment Of Human Breast Cancer Cells With Okadaic Acidmentioning

confidence: 99%

Inflammation and IGF‐I activate the Akt pathway in breast cancer

Prueitt

Boersma

Howe

et al. 2006

Intl Journal of Cancer

111

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Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p < 0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (p 0.05; Spearman rank correlation). The association with Akt phosphorylation at Thr308 remained statistically significant in the multivariate analysis. Akt pathway activation was not associated with overall survival in the unstratified analysis, but we observed a statistical interaction between Akt phosphorylation and tumor phagocyte density on breast cancer survival (p interaction < 0.05). We further corroborated our findings in cell culture models by demonstrating that ANA-1 macrophages, nitric oxide and prostaglandin E 2 induce Akt phosphorylation in human breast cancer cells. In summary, a proinflammatory environment was found to activate the Akt pathway in breast cancer, and may modify the association between the Akt phosphorylation status and breast cancer survival. ' 2006 Wiley-Liss, Inc.Key words: breast cancer; Akt; inflammation; insulin-like growth factor; survival The Akt family of serine/threonine protein kinases are putative oncogenes that enhance the survival of various cell types. 1,2 The 3 closely related Akt isoforms induce cell proliferation and soft agar growth, and disrupt the acinar architecture of human mammary cells, but do not induce transformation by themselves. 3-5 Akt activation requires 2 critical phosphorylation steps at Thr308 and Ser473. The phosphorylation is induced by ligand-mediated activation of growth factor receptors and receptor tyrosine kinases. Insulin-like growth factor I (IGF-I), insulin and the epidermal growth factor are ligands that activate Akt through the receptormediated pathway. 1,6 The phosphorylation of membrane-bound Akt establishes the full Akt kinase activity and induces Akt translocation into the cytosol and nucleus. 7-10 Activated Akt phosphorylates a number of downstream targets such as BAD, caspase-9, p21, p27, GSK3b, Mdm2, mTOR, IKKa and others. 1,11,12 The phosphorylation of BAD and caspase-9 blocks the apoptotic activity of the 2 proteins and raises the threshold for apoptosis. [13][14][15] Thus, tumors that show a high phosphorylation of BAD and caspase-9 may have a ...

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“…PP2A was identified as the main phosphatase involved in the regulation of Akt in rat adipocytes. 22 It can be coprecipitated with Akt and coexpression of the catalytic subunit of PP2A with Akt inhibited Akt activity. 23 The activation of PP2A by N-ethylmaleimide, ceramide, palmitate or integrin a2b1 inhibits Akt phosphorylation.…”

Section: Mechanisms Of Akt Regulationmentioning

confidence: 99%

“…98,107,108 In the past few years, the results of multiple studies have shown that PP2A or PP1 can participate in the regulation of PI3-K-Akt pathway through dephosphorylation of activated Akt and that these proteins can function as the major phosphatases for Akt in some systems. [21][22][23][24][25][26] Recent studies also show that alteration of PP2A and PP1 gene expression is associated with multiple human cancers. The PP2R1B gene that encodes the b isoform of the A subunit of PP2A is located in a region showing high-frequency LOH.…”

Section: Genetic Perturbation and Dysregulation Of The Pi3-k-akt Pathwaymentioning

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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Protein phosphatase 2A is the main phosphatase involved in the regulation of protein kinase B in rat adipocytes

Cited by 127 publications

References 54 publications

Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells

Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells

Inflammation and IGF‐I activate the Akt pathway in breast cancer

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

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