PI3K: Downstream AKTion Blocks Apoptosis

Franke, Thomas; Kaplan, David R.; Cantley, Lewis C.

doi:10.1016/s0092-8674(00)81883-8

Cited by 1,577 publications

(1,160 citation statements)

References 16 publications

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“…All these three signal transduction cascades have been shown to be involved in antiapoptotic effects of Epo on erythroblasts. 14,15 Akt, a serine/threonine protein kinase, was identified as a downstream component in survival signaling through PI3-K. 23 Western blot analysis of retinal lysates of Epo-treated rats revealed a significant upregulation of p-Akt when compared to vehicle-treated controls (Figure 3a). The expression of the unphosphorylated, inactive Akt protein was the same in all samples analyzed.…”

Section: Epo Modulates Three Distinct Intracellular Neuroprotective Pmentioning

confidence: 99%

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

Sättler¹,

Merkler

Maier³

et al. 2004

Cell Death Differ

164

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In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.

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Section: Epo Modulates Three Distinct Intracellular Neuroprotective Pmentioning

confidence: 99%

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

Sättler¹,

Merkler

Maier³

et al. 2004

Cell Death Differ

164

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“…Other MAPKs, such as c-Jun N-terminal kinase (JNK) and p38MAPK (p38), may also be involved in the downstream signaling from Ras (Lin et al, 1995). On the other hand, P13K activates other protein kinases, such as AKT and BTK, by generating phospholipid activators for these enzymes (Franke et al, 1997;Uckun, 1998). Our experiments using gene transfer and pharmacological inhibitors suggest that persistent activities of Ras and its down-stream ERK pathway may be important for the suppression of erythroid di erentiation and maintenance of proliferative potential in SKT6 cell line.…”

Section: Introductionmentioning

confidence: 99%

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

et al. 2000

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The role of Ras and MAP kinases (MAPKs) in the regulation of erythroid di erentiation was studied using a cell line (SKT6) derived from Friend virus (Anemic strain)-induced murine erythroleukemia. This cell line undergoes di erentiation in vitro in response to erythropoietin (EPO) or other chemical inducers such as dimethylsulfoxide (DMSO). When a constitutively active ras mutant (ras12V) was expressed in SKT6 cells, EPO-induced di erentiation was inhibited. Conversely, a dominant negative ras mutant (ras17N) induced di erentiation even in the absence of EPO, suggesting that the basal Ras activity is essential for the maintenance of the undi erentiated phenotype and proliferative potential in this cell line. Rapid inactivation of ERK was observed after expression of ras17N. Slow but signi®cant inactivation of ERK was also observed during EPOinduced di erentiation. Furthermore, overexpression of a constitutively active mutant of ERK-activating kinase (MAPKK) was found to suppress erythroid di erentiation, while pharmacological inhibition of MAPKK induced di erentiation. These ®ndings suggest that down-regulation of Ras/ERK signaling pathway may be an essential event in EPO-induced erythroid di erentiation in this system. Oncogene (2000) 19, 1500 ± 1508.

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confidence: 99%

“…Its activation has been implicated in a number of human cancers by promoting proliferation and inhibiting apoptosis caused by various death stimuli (Del Peso et al, 1997;Franke et al, 1997;Kulik et al, 1997). AKT is activated in response to survival signals from growth factors or cytokines via mechanisms involving PI3-K and PDK-1 (Alessi et al, 1997;Franke et al, 1997;Kulik et al, 1997;Bellacosa et al, 1998). Upregulation of AKT by mutation of PTEN (a tumour suppressor gene that antagonises AKT pathway) or amplification PIK3CA (encodes catalytic subunit of PI3-K) were reported in a number of human cancers including breast carcinoma (Vivanco and Sawyers, 2002;Lee et al, 2005;Levine et al, 2005).…”

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confidence: 99%

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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Activation of kinases signalling pathways contributes to various malignant phenotypes in human cancers, including breast tumour. To examine the possible activation of these signalling molecules, we examined the phosphorylation status in 12 protein kinases and transcription factors in normal primary human mammary epithelial cells, telomerase-immortalised human breast epithelial cell line, and two breast cancer lines, MDA-MB-468 and MCF-7, using Kinexus phosphorylated protein screening assays. The phosphorylation of FAK, mTOR, p70S6K, and PDK-1 were elevated in both breast cancer cell lines, whereas the phosphorylation of AKT, EGFR, ErbB2/ Her2, PDGFR, Shc, and Stat3 were elevated in only one breast cancer line compared to normal primary mammary epithelial cells and telomerase-immortalised breast epithelial cells. The same findings were confirmed by Western blotting and by kinase assays. We further substantiated the phosphorylation status of these molecules in tissue microarray slides containing 89 invasive breast cancer tissues as well as six normal mammary tissues with immunohistochemistry staining using phospho-specific antibodies. Consistent findings were obtained as greater than 70% of invasive breast carcinomas expressed moderate to high levels of phosphorylated PDK-1, AKT, p70S6K, and EGFR. In sharp contrast, phosphorylation of the same proteins was nearly undetectable or was at low levels in normal mammary tissues under the same assay. Elevated phosphorylation of PDK-1, AKT, mTOR, p70S6K, S6, EGFR, and Stat3 were highly associated with invasive breast tumours (Po0.05). Taken together, our results suggest that activation of these kinase pathways by phosphorylation may in part account for molecular pathogenesis of human breast carcinoma. Particularly, moderate to high level of PDK-1 phosphorylation was found in 86% of high-grade metastasised breast tumours. This is the first report demonstrating phosphorylation of PDK-1 is frequently elevated in breast cancer with concomitantly increased phosphorylation of downstream kinases, including AKT, mTOR, p70S6K, S6, and Stat3. This finding thus suggested PDK-1 may promote oncogenesis in part through the activation of AKT and p70S6K and rationalised that PDK-1 as well as downstream components of PDK-1 signalling pathway may be promising therapeutic targets to treat breast cancer. Breast cancer remains to be a major cause of death in women worldwide, despite improvements in cancer prevention, early detection, treatment, and understanding the molecular pathogenesis. It hence demands an urgent need to unveil the exact mechanism of oncogenesis and tumour progression, which may prelude the development of new strategies for treatment. Breast carcinoma emerges through multistep processes progressing from hyperplasia to premalignant change, in situ carcinoma, invasion, and distal metastasis, in concomitant with gain of oncogenic activities and loss of tumour suppressor gene functions.Protein kinases have been implicated in playing crucial roles in regulating cell growth, met...

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PI3K: Downstream AKTion Blocks Apoptosis

Cited by 1,577 publications

References 16 publications

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

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