Role of PI 3-kinase, Akt and Bcl-2–related proteins in sustaining the survival of neurotrophic factor–independent adult sympathetic neurons

Orike, Nina; Middleton, Gayle; Borthwick, Emma B.; Buchman, Vladimir L.; Cowen, T.; Davies, Alun M.

doi:10.1083/jcb.200101068

Cited by 107 publications

(70 citation statements)

References 85 publications

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“…z-VAD-FMK prevents cell death by inhibiting cysteine proteases that execute the cell death pathway (52,53,68,69). z-VAD-FMK was added at the time of transfection of cells with hairpin siRNA vectors and the ngn3 and GFP expression vectors, and the cells were maintained in the presence of the inhibitor for the duration of the experiment.…”

Section: Resultsmentioning

confidence: 99%

Akt Regulates Basic Helix-Loop-Helix Transcription Factor–Coactivator Complex Formation and Activity during Neuronal Differentiation

Vojtek¹,

Taylor²,

DeRuiter

et al. 2003

Molecular and Cellular Biology

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Neural basic helix-loop-helix (bHLH) transcription factors regulate neurogenesis in vertebrates.Signaling by peptide growth factors also plays critical roles in regulating neuronal differentiation and survival. Many peptide growth factors activate phosphatidylinositol 3-kinase (PI3K) and subsequently the Akt kinases, raising the possibility that Akt may impact bHLH protein function during neurogenesis. Here we demonstrate that reducing expression of endogenous Akt1 and Akt2 by RNA interference (RNAi) reduces neuron generation in P19 cells transfected with a neural bHLH expression vector. The reduction in neuron generation from decreased Akt expression is not solely due to decreased cell survival, since addition of the caspase inhibitor z-VAD-FMK rescues cell death associated with loss of Akt function but does not restore neuron formation. This result indicates that Akt1 and Akt2 have additional functions during neuronal differentiation that are separable from neuronal survival. We show that activated Akt1 enhances complex formation between bHLH proteins and the transcriptional coactivator p300. Activated Akt1 also significantly augments the transcriptional activity of the bHLH protein neurogenin 3 in complex with the coactivators p300 or CBP. In addition, inhibition of endogenous Akt activity by the PI3K/Akt inhibitor LY294002 abolishes transcriptional cooperativity between the bHLH proteins and p300. We propose that Akt regulates the assembly and activity of bHLH-coactivator complexes to promote neuronal differentiation.

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Section: Resultsmentioning

confidence: 99%

Akt Regulates Basic Helix-Loop-Helix Transcription Factor–Coactivator Complex Formation and Activity during Neuronal Differentiation

Vojtek¹,

Taylor²,

DeRuiter

et al. 2003

Molecular and Cellular Biology

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“…Akt plays a major role in cell survival and acts as an anti-apoptotic agent by affecting many downstream effectors such as BAD (Bcl-2-associated death protein), FKHR (forkhead transcription factor), and caspase-3 (Khwaja, 1999;Orike et al, 2001). Akt can also exert a positive effect on nuclear factor-B (NF-B) function by phosphorylation and activation of IB kinase (Cantley, 2002), and NF-B can enter the nucleus to initiate transcription of anti-apoptotic factors.…”

Section: Discussionmentioning

confidence: 99%

Nonredundant Role of Akt2 for Neuroprotection of Rod Photoreceptor Cells from Light-Induced Cell Death

et al. 2007

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The Akt kinases mediate cell survival through phosphorylation and inactivation of apoptotic machinery components. Akt signaling provides a trophic signal for transformed retinal neurons in culture, but the in vivo role of Akt activity is unknown. In this study, we found that all three Akt isoforms were expressed in rod photoreceptor cells. We investigated the functional roles of Akt1 and Akt2, two of the isoforms of Akt, and their biological significance in light-induced retinal degeneration. Consistent with the hypothesis that Akt activity is important to circumvent stress-induced apoptosis, herein we report the novel finding that rod photoreceptor cells in Akt2 knock-out mice exhibited a significantly greater sensitivity to stress-induced cell death than rods in heterozygous or wild-type mice. Under similar conditions, Akt1 deletion had no effect on the retina. The presence of three Akt isoforms in the retina is suggestive of a functional redundancy; however, our studies clearly demonstrate that, under stress, Akt1 and Akt3 cannot complement the specific survival signals driven by Akt2. Furthermore, we show that Akt2 is specially activated is response to light stress. The results presented in this study provide the first direct evidence that Akt2 has a nonredundant neuroprotective role in photoreceptor survival and maintenance.

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“…Consistent with this origin, NBs exhibit varying degrees of neurotrophin tyrosine kinase receptor TrkA expression, which regulates sympathetic nervous system development (Pahlman and Hedborg, 2000;Orike et al, 2001). TrkA expression in NB is considered to be clinically relevant and unveils a pivotal function for this receptor in regulating tumour behaviour (Nakagawara et al, 1992;Nakagawara, 2001).…”

Section: Introductionmentioning

confidence: 99%

The neuroblastoma tumour-suppressor TrkAI and its oncogenic alternative TrkAIII splice variant exhibit geldanamycin-sensitive interactions with Hsp90 in human neuroblastoma cells

et al. 2009

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Hsp90 chaperones stabilize many tyrosine kinases including several oncogenes, which are inhibited or induced to degrade by the Hsp90 inhibitor geldanamycin (GA). As a consequence, GA has been developed for future chemotherapeutic use in several tumour types including neuroblastoma (NB). Alternative splicing of the neurotrophin receptor tyrosine kinase TrkA may have a pivotal function in regulating NB behaviour, with reports suggesting that tumour-suppressing signals from TrkA may be converted to oncogenic signals by stress-regulated alternative TrkAIII splicing. Within this context, it is important to know whether Hsp90 interacts with TrkA variants in NB cells and how GA influences this. Here, we report that both TrkAI and TrkAIII are Hsp90 clients in human NB cells. TrkAI exhibits GA-sensitive interaction with Hsp90 required for receptor endoplasmic reticulum export, maturation, cell surface stabilization and ligandmediated activation, whereas TrkAIII exhibits GAsensitive interactions with Hsp90 required for spontaneous activity and to a lesser extent stability. We show that GA inhibits proliferation and induces apoptosis of TrkAI expressing NB cells, whereas TrkAIII reduces the sensitivity of NB cells to GA-induced elimination. Our data suggest that GA-sensitive interactions with Hsp90 are critical for both TrkAI tumour suppressor and TrkAIII oncogenic function in NB and that TrkAIII expression exerts a negative impact on GA-induced NB cell eradication, which can be counteracted by a novel TrkAIII-specific peptide nucleic acid inhibitor.

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Role of PI 3-kinase, Akt and Bcl-2–related proteins in sustaining the survival of neurotrophic factor–independent adult sympathetic neurons

Cited by 107 publications

References 85 publications

Akt Regulates Basic Helix-Loop-Helix Transcription Factor–Coactivator Complex Formation and Activity during Neuronal Differentiation

Akt Regulates Basic Helix-Loop-Helix Transcription Factor–Coactivator Complex Formation and Activity during Neuronal Differentiation

Nonredundant Role of Akt2 for Neuroprotection of Rod Photoreceptor Cells from Light-Induced Cell Death

The neuroblastoma tumour-suppressor TrkAI and its oncogenic alternative TrkAIII splice variant exhibit geldanamycin-sensitive interactions with Hsp90 in human neuroblastoma cells

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