Cellular survival: a play in three Akts

Datta, Sandeep Robert; Brunet, Anne; Greenberg, Michael E.

doi:10.1101/gad.13.22.2905

Cited by 3,859 publications

(3,525 citation statements)

References 232 publications

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“…The anti-apoptotic events regulated by Akt are complex and include phosphorylation and inactivation of pro-apoptotic proteins engaged in mitochondrial apoptosis, such as Bad and procaspase-9, 40 as well as increased expression of anti-apoptotic proteins including IAPs and Bcl-xL. 41,42 Akt was first identified as a positive regulator of survivin expression in endothelial cells, 21,24 and subsequent studies pinpointed survivin as an anti-apoptotic target responsive to cytokines and other pro-survival factors in leukemia and prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Belyanskaya¹,

Hopkins-Donaldson²,

Kurtz³

et al. 2005

Intl Journal of Cancer

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The inhibitor of apoptosis protein (IAP) survivin is overexpressed in many tumors but is absent in most normal adult tissues. We report high levels of survivin expression in small cell lung cancer (SCLC), and describe the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in survivin upregulation. Moreover, the cytoprotective function of survivin in response to the anti-cancer agent cisplatin (CDDP) was investigated. Negative modulation of PI3K/ Akt using pharmacological inhibitors or dominant negative Akt (DN-Akt) decreased Akt kinase activity and resulted in decreased survivin expression and phosphorylation on Thr34, whereas transfection of constitutively active Akt (CA-Akt) increased survivin expression and phosphorylation. Interestingly, we found that treatment of SCLC cells with CDDP further increased survivin expression in a cell cycle independent manner by activation of Akt. CA-Akt or lentiviral survivin also inhibited apoptosis induced by CDDP, whereas DN-Akt or survivin-specific RNA interference sensitized cells to CDDP. We identified survivin as an anti-apoptotic protein in SCLC cells that is regulated by Akt, and demonstrate that treatment with the DNA damaging agent CDDP activates the PI3K/Akt/survivin pathway that in part protects cells from drug-induced apoptosis. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Belyanskaya¹,

Hopkins-Donaldson²,

Kurtz³

et al. 2005

Intl Journal of Cancer

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“…Therefore, when Akt is inhibited these other pathways might be activated even in the presence of an inhibitor of the JNK pathways such as CEP-1347. Candidates for these pathways include glycogen synthase kinase (GSK)-3 and the Forkhead class of transcription factors (Datta et al 1999).…”

Section: Cep-1347 Provides Transient Survival Of Granule Cellsmentioning

confidence: 99%

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Harris¹,

Maroney²,

Johnson

2002

Journal of Neurochemistry

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Cerebellar granule neurons grown in high potassium undergo rapid apoptosis when switched to medium containing 5 mM potassium, a stimulus mimicking deafferentation. This cell death can be blocked by genetic deletion of Bax, a member of the pro-apoptotic Bcl-2 family, cycloheximide an inhibitor of macromolecular synthesis or expression of dominant-negative c-jun. These observations suggest that Bax activation is the result of c-jun target gene(s) up-regulation following trophic withdrawal. Candidate genes include the BH3-only Bcl-2 family members Dp5 and Bim. The molecular mechanisms underlying granule cell neuronal apoptosis in response to low potassium were investigated using CEP-1347 (KT7515), an inhibitor of the MLK family of JNKKK. CEP-1347 provided protection of potassium-serum-deprived granule cells, but such neuroprotection was not long term. The incomplete protection was not due to incomplete blockade of the JNK signaling pathway because c-jun phosphorylation as well as induction of c-jun RNA and protein were completely blocked by CEP-1347. Following potassium-serum deprivation the JNKK MKK4 becomes phosphorylated, an event blocked by CEP-1347. Cells that die in the presence of CEP-1347 activate caspases; and dual inhibition of caspases and MLKs has additive, not synergistic, effects on survival. A lack of synergism was also seen with the p38 inhibitor SB203580, indicating that the neuroprotective effect of the JNK pathway inhibitor cannot be explained by p38 activation. Activation of the JNK signaling pathway seems to be a key event in granule cell apoptosis, but these neurons cannot survive long term in the absence of sustained PI3 kinase signaling. Neuronal survival is controlled in vivo by both retrograde signaling from neuronal targets as well as anterogradely via synaptic input. Cerebellar granule neurons are one such population whose survival is regulated by retrograde and anterograde signaling both in vivo and in vitro. In the lurcher mouse, cerebellar granule neurons die in response to the death of their targets, Purkinje neurons (Wetts and Herrup 1982). If the afferent activity to granule neurons is eliminated by mossy fiber axotomy, they undergo massive apoptosis (Borsello et al. 2000). These findings have been mimicked in vitro. Target-derived neurotrophic factors such as brain-derived growth factor (BDNF) and insulin-like growth factor (IGF)-1 promote the survival of cerebellar granule cells (Lindholm et al. 1993;Miller et al. 1997b). These neurons also undergo massive cell death when deafferentation is mimicked by removing the survival stimulus provided by depolarizing levels of potassium (Gallo et al. 1987). Abbreviations used: ASK, apoptosis signal regulating kinase 1; BAF, boc-aspartyl(OMe)-fluoromethylketone; BME, b-mercaptoethanol; CMV, cytomegalovirus; DEVD-amc, DEVD-aminomethylcoumarin; DIV, days in vitro; DTT, dithiothreitol; IP3, inositol-1,4,5-triphosphate; JNK, c-Jun N-terminal kinase; JNKKK, JNK kinase kinase; K5 ) S, buffer containing 5 mM KCl without serum; K25 + S, buf...

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“…However, in human glioma cell lines, SPARC increases invasion in vitro and in vivo (Schultz et al, 2002;Rich et al, 2003). SPARC also promotes cell survival through the activation of AKT/protein kinase B (Shi et al, 2004), an intracellular serine/threonine kinase known to inhibit apoptosis and known to be activated in cancer (Datta et al, 1999). We recently demonstrated that exogenous SPARC protein induces activating phosphorylation of AKT within minutes in a concentration-dependent manner, and stable overexpression of SPARC also increases AKT phosphorylation (Shi et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases

et al. 2007

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Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in several solid cancers, including malignant gliomas, upon adoption of metastatic or invasive behaviors. SPARC expression in glioma cells promotes invasion and survival under stress, the latter process dependent on SPARC activation of AKT. Here we demonstrate that downregulation of SPARC expression with short interfering RNA (siRNA) in glioma cells decreased tumor cell survival and invasion. SPARC siRNA reduced the activating phosphorylation of AKT and two cytoplasmic kinases, focal adhesion kinase (FAK) and integrin-linked kinase (ILK). We determined the contributions of FAK and ILK to SPARC effects using SPARC protein and cell lines engineered to overexpress SPARC. SPARC activated FAK and ILK in glioma cells previously characterized as responsive to SPARC. Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone. Decreased SPARC-mediated AKT activation correlated with a reduction in SPARC-dependent invasion and survival upon the downregulation of FAK and/or ILK expression. These data further demonstrate the role of SPARC in glioma tumor progression through the activation of intracellular kinases that may provide novel therapeutic targets for advanced cancers.

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Cellular survival: a play in three Akts

Cited by 3,859 publications

References 232 publications

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases

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