The activation of Akt/PKB signaling pathway and cell survival

Song, Gang; Ouyang, Gaoliang; Bao, Shideng

doi:10.1111/j.1582-4934.2005.tb00337.x

Cited by 1,625 publications

(1,305 citation statements)

References 101 publications

(114 reference statements)

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“…IL-4 stimulated the tyrosine phosphorylation of IRS2, its association with the p85 subunit of PI-3K, and the tyrosine phosphorylation of STAT6 in CH31.We next examined the ability of IL-4 to regulate proteins involved in mitochondria-regulated apoptosis downstream from IRS2/PI-3K or from STAT6 ( Figure 6). Active Akt has been termed a master regulator of cell survival [44]. Consistent with this notion, we found that CH31 cells contain Akt constitutively phosphorylated on S 473 (pAkt), a marker of its activation ( Figure 6, [45]).…”

Section: Effects Of Il-4 Signaling On the Pi-3k/akt Pathway And Protesupporting

confidence: 65%

“…Akt is a major regulator of cellular survival since its activity is directed toward suppressing the activities and/or expression of multiple pro-apoptotic proteins [44,45]. Phosphorylation of S 136 on BAD (pBAD) by Akt suppresses BAD activity so that pBAD cannot antagonize the pro-survival functions of Bcl-2 and Bcl-xL [47,48].…”

Section: Discussionmentioning

confidence: 99%

“…pAkt activity controls both the expression and activities of multiple pro-apoptotic proteins such as BAD, GSK-3β, IKK, caspase-9 and the forkhead (FKHR) transcription factors [44][45][46]. BAD can perturb the mitochondrion by antagonizing the survival functions of Bcl-2 and Bcl-xL, and phosphorylation of S 136 on BAD (pBAD) by Akt suppresses BAD activity [47,48].…”

Section: Effects Of Il-4 Signaling On the Pi-3k/akt Pathway And Protementioning

confidence: 99%

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IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

Carey

Семенова

et al. 2007

Cell Res

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Interleukin-4 (IL-4) promotes lymphocyte survival and protects primary lymphomas from apoptosis. Previous studies reported differential requirements for the signal transducer and activator of transcription 6 (STAT6) and IRS2/phosphatidylinositol 3 kinase (PI-3K) signaling pathways in mediating the IL-4-induced protection from Fas-mediated apoptosis. In this study, we characterized IL-4-activated signals that suppress anti-IgM-mediated apoptosis and growth arrest of CH31, a model B-cell lymphoma line. In CH31, anti-IgM treatment leads to the loss of mitochondrial membrane potential, phospho-Akt, phospho-CDK2, and c-myc protein. These losses are followed by massive induction of p27 Kip1 protein expression, cell cycle arrest, and apoptosis. Strikingly, IL-4 treatment prevented or reversed these changes. Furthermore, IL-4 suppressed the activation of caspases 9 and 3, and, in contrast to previous reports, induced the phosphorylation (deactivation) of BAD. IL-4 treatment also induced expression of BclxL, a STAT6-dependent gene. Pharmacologic inhibitors and dominant inhibitory forms of PI-3K and Akt abrogated the anti-apoptotic function of IL-4. These results suggest that the IL-4 receptor activates several signaling pathways, with the Akt pathway playing a major role in suppression of the apoptotic program activated by anti-IgM.

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Section: Effects Of Il-4 Signaling On the Pi-3k/akt Pathway And Protesupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Il-4 Signaling On the Pi-3k/akt Pathway And Protementioning

confidence: 99%

See 1 more Smart Citation

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

Carey

Семенова

et al. 2007

Cell Res

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“…It is, however, in agreement with reports that showed inhibition of cisplatin-induced, p53-dependent apoptosis by LY294.002 [39]. Although the PI3-K/PKBpathway is mainly known for its pro-survival activity [50], it contributes in this complex context to apoptosis-induction. Additionally, it postponed MiliA-dependent AP-1 DNA-binding activity.…”

Section: Discussionsupporting

confidence: 92%

Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53

et al. 2008

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The fungal alkaloid militarinone A (MiliA) was recently found to stimulate neuronal outgrowth in PC-12 cells by persistant activation of pathways that are also involved in NGF-mediated differentiation, namely the PI3-K/PKB and the MEK/ERK pathways. Application of equal concentrations of MiliA to other cells such as the murine neuroblastoma cell line N2a resulted in immediate onset of apoptosis by nuclear translocation of apoptosis inducing factor (AIF), activation of caspases and c-Jun/AP-1 transcription factor without an intermediate differentiated phenotype, although minor transient phosphorylation of PKB and MAPK as well as activation of NF-jB were also observed. Translocation of AIF was preceded by p53 phosphorylation at Ser15 and blocked by pifithrin a, a known inhibitor of p53-transcriptional activity. We here show that both cell types activate the same pathways albeit in different time scales. This is mainly due to contrasting basal expression levels of p53, which in turn regulates expression of AIF. In PC-12 cells, continuous activation of these pathways after prolonged treatment with 40 lM MiliA first led to up-regulation of p53, phosphorylation of p53, release of AIF from mitochondria and its translocation into the nucleus. Additionally, also activation of the c-Jun/ AP-1 transcription factor was observed, and PC-12 cells subsequently underwent apoptosis 48-72 h post-treatment. We report that similar pathways working on different levels are able to initially shape very divergent cellular responses.

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“…For both types of receptors, TRAF6 links activation signals to cellular survival pathways, including PI3 K/Akt [38]. Akt enhances cell survival through regulation of protein phosphorylation, transcription, and metabolic regulation of apoptosis [47]. In the pathway revealed here, Akt may play a role in modulating pro-apoptotic proteins, activating anti-apoptotic molecules, or changing subcellular locations or interactions between these classes of molecules.…”

Section: Discussionmentioning

confidence: 87%

Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

Benson

Hostager²,

Bishop

2006

Eur J Immunol

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The activation molecule CD40 and the death receptor CD95/Fas play important roles in regulating B cells so that effective antimicrobial immunity occurs without autoimmunity. CD40 signaling increases CD95 expression, sensitizing cells to apoptosis, but sustained CD40 signals rescue B cells from CD95 killing. Here we describe a mechanism of early CD40-mediated rescue from CD95-induced apoptosis in B cells. Maximal rescue was achieved when CD40 signals were given within 1-2 h of initiating CD95 apoptosis. CD40 signaling did not block association of Fas-associated death domain-containing protein with CD95, but decreased CD95-induced activation of caspases 3 and 8. Rapid CD40 rescue did not require NF-jB activation and was independent of de novo protein synthesis, but was dependent upon active PI3 K. Signaling via a CD40 mutant that does not bind TNFR-associated factor (TRAF)1, TRAF2, and TRAF3 rescued B cells from CD95-induced apoptosis. TRAF1/2/3-independent rescue was confirmed in B cell lines made deficient in these TRAF molecules by gene targeting. In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis. IntroductionB cells integrate many signals that direct proliferation and differentiation into Ig-secreting plasma cells or longlived memory cells. Ultimately, activated B cells can be eliminated through apoptosis, which is important for maintaining immune tolerance and homeostasis [1,2]. Molecules of the TNFR family play critical roles in regulating the balance between B cell activation and apoptosis. CD40 signals allow B cells to proliferate, differentiate, switch isotype, form GC, and become memory cells [3][4][5]. CD40 stimulation also induces upregulation of other members of the TNFR family, including the death receptor CD95/Fas [6].The importance of CD95 in maintaining lymphocyte homeostasis and tolerance is highlighted by the human disease autoimmune lymphoproliferative syndrome (ALPS), caused by mutations in the CD95 signaling pathway [7,8] autoantibodies are produced, and systemic autoimmunity develops [9]. Expression of the CD95 transgene exclusively in T cells of lpr/lpr mice is sufficient to decrease lymphadenopathy, splenomegaly, and the accumulation of abnormal T cells, but these mice still produce autoantibodies, causing deposition of immune complexes in kidney glomeruli [10]. In contrast, expression of the CD95 transgene in both B and T cells reduces the levels of serum Ig, autoimmune symptoms, and mortality [11]. Thus, CD95 signaling in B cells is crucial for maintaining peripheral tolerance and preventing autoimmunity. When CD95 is oligomerized, either by binding to its ligand on T cells (CD95L) or by Ab against its extracellular domain, it recruits the adaptor molecule Fas-associated death domain-containing protein (FADD) and procaspase 8 into a complex called the deathinducing signaling complex (DISC) that cleaves pro...

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The activation of Akt/PKB signaling pathway and cell survival

Cited by 1,625 publications

References 101 publications

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53

Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

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