Akt2, but not Akt1, is required for cell survival by inhibiting activation of JNK and p38 after UV irradiation

Ma, Kim; Kim, Hyung Jun; Hj, Jee; Aj, Kim; Ys, Bae; Ss, Bae; Yun, Jimmy

doi:10.1038/onc.2008.487

Cited by 20 publications

(19 citation statements)

References 26 publications

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“…The other isoform which is expressed at high levels in neuroblastoma cell lines, AKT1 , does not possess a miR-184 target site, remains constant in all of our experiments, and does not rescue the cells from the effects of miR-184 over-expression. This is consistent with findings that AKT2 does not share complementary functions with AKT1 regarding cell invasiveness and survival in other forms of cancer [32,33]. …”

Section: Discussionsupporting

confidence: 93%

MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2

et al. 2010

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BackgroundNeuroblastoma is a paediatric cancer of the sympathetic nervous system. The single most important genetic indicator of poor clinical outcome is amplification of the MYCN transcription factor. One of many down-stream MYCN targets is miR-184, which is either directly or indirectly repressed by this transcription factor, possibly due to its pro-apoptotic effects when ectopically over-expressed in neuroblastoma cells. The purpose of this study was to elucidate the molecular mechanism by which miR-184 conveys pro-apoptotic effects.ResultsWe demonstrate that the knock-down of endogenous miR-184 has the opposite effect of ectopic up-regulation, leading to enhanced neuroblastoma cell numbers. As a mechanism of how miR-184 causes apoptosis when over-expressed, and increased cell numbers when inhibited, we demonstrate direct targeting and degradation of AKT2, a major downstream effector of the phosphatidylinositol 3-kinase (PI3K) pathway, one of the most potent pro-survival pathways in cancer. The pro-apoptotic effects of miR-184 ectopic over-expression in neuroblastoma cell lines is reproduced by siRNA inhibition of AKT2, while a positive effect on cell numbers similar to that obtained by the knock-down of endogenous miR-184 can be achieved by ectopic up-regulation of AKT2. Moreover, co-transfection of miR-184 with an AKT2 expression vector lacking the miR-184 target site in the 3'UTR rescues cells from the pro-apoptotic effects of miR-184.ConclusionsMYCN contributes to tumorigenesis, in part, by repressing miR-184, leading to increased levels of AKT2, a direct target of miR-184. Thus, two important genes with positive effects on cell growth and survival, MYCN and AKT2, can be linked into a common genetic pathway through the actions of miR-184. As an inhibitor of AKT2, miR-184 could be of potential benefit in miRNA mediated therapeutics of MYCN amplified neuroblastoma and other forms of cancer.

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Section: Discussionsupporting

confidence: 93%

MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2

et al. 2010

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“…We now show that this effect is mainly dependent on Akt2. This conclusion is supported by other results indicating that Akt2 inhibits apoptosis during myogenic differentiation or UV irradiation (71,72). Moreover, depletion of Akt2 but not of Akt1 induces tumor regression (73).…”

Section: Discussionsupporting

confidence: 79%

A Switch in Akt Isoforms Is Required for Notch-Induced Snail1 Expression and Protection from Cell Death

Frías

Lambies

Viñas-Castells

et al. 2016

Molecular and Cellular Biology

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b Notch activation in aortic endothelial cells (ECs) takes place at embryonic stages during cardiac valve formation and induces endothelial-to-mesenchymal transition (EndMT). Using aortic ECs, we show here that active Notch expression promotes EndMT, resulting in downregulation of vascular endothelial cadherin (VE-cadherin) and upregulation of mesenchymal genes such as those for fibronectin and Snail1/2. In these cells, transforming growth factor ␤1 exacerbates Notch effects by increasing Snail1 and fibronectin activation. When Notch-downstream pathways were analyzed, we detected an increase in glycogen synthase kinase 3␤ (GSK-3␤) phosphorylation and inactivation that facilitates Snail1 nuclear retention and protein stabilization. However, the total activity of Akt was downregulated. The discrepancy between Akt activity and GSK-3␤ phosphorylation is explained by a Notch-induced switch in the Akt isoforms, whereby Akt1, the predominant isoform expressed in ECs, is decreased and Akt2 transcription is upregulated. Mechanistically, Akt2 induction requires the stimulation of the ␤-catenin/TCF4 transcriptional complex, which activates the Akt2 promoter. Active, phosphorylated Akt2 translocates to the nucleus in Notch-expressing cells, resulting in GSK-3␤ inactivation in this compartment. Akt2, but not Akt1, colocalizes in the nucleus with lamin B in the nuclear envelope. In addition to promoting GSK-3␤ inactivation, Notch downregulates Forkhead box O1 (FoxO1), another Akt2 nuclear substrate. Moreover, Notch protects ECs from oxidative stress-induced apoptosis through an Akt2-and Snail1-dependent mechanism.

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“…The study also pointed out that PINCH-1 could regulate the ERK-Bim pathway in protecting cancer cells from apoptosis. As AKT activation has been shown to suppress JNK, which in turn downregulates ERK [30,31] , it is probable that PINCH-1 regulates all these pathways by modulating AKT phosphorylation. Further investigation can be performed to verify the modulation method.…”

Section: Discussionmentioning

confidence: 99%

Early Activation of PINCH/ Glycogen-Synthase Kinase 3β/ERK Pathway in Obstructive Nephropathy Rat Model

Jia

Li²,

Gu³

et al. 2016

Am J Nephrol

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Background: Despite a previous study showing that PINCH-1 exerts an important role in regulating TGF-β1-mediated mesenchymal transition through its interaction with integrin-linked kinase, relatively little is known about the role of PINCH in the obstructive nephropathy. Methods: To construct a rat model of renal interstitial fibrosis and obstructive nephropathy, unilateral ureteral obstruction (UUO) was used. Hematoxylin and eosin and Masson staining were used in histologic examinations. Quantificational reverse transcription-PCR was used to analyze the mRNA expression level. Western blot and the immunohistochemistry staining were used to detect the protein levels. Results: Histologic examination showed that slight interstitial fibrosis and tubular atrophy existed in the kidney of UUO rats. PINCH, alpha-smooth muscle actin, vascular endothelial growth factor and connective tissue growth factor were markedly induced in the kidney of the UUO rats. However, the expression level of E-cadherin was markedly suppressed in the kidney of the UUO rats. Moreover, both JUN and phosphorylation of JUN proteins were significantly decreased in the kidney of the UUO rats. Conversely, phosphorylation of ERK1/2 and glycogen-synthase kinase 3β (GSK3β) were markedly induced in UUO rats compared to that in sham rats. However, ERK1/2 proteins showed no statistically significant difference between UUO and sham groups. Conclusions: PINCH/GSK3β/ERK pathway was early molecular responses to obstructed kidney induced by UUO in rat.

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Akt2, but not Akt1, is required for cell survival by inhibiting activation of JNK and p38 after UV irradiation

Cited by 20 publications

References 26 publications

MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2

MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2

A Switch in Akt Isoforms Is Required for Notch-Induced Snail1 Expression and Protection from Cell Death

Early Activation of PINCH/ Glycogen-Synthase Kinase 3β/ERK Pathway in Obstructive Nephropathy Rat Model

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