Requirement for Phosphatidylinositol-3 Kinase in the Prevention of Apoptosis by Nerve Growth Factor

Yao, Ryoji; Cooper, Geoffrey M.

doi:10.1126/science.7701324

Cited by 1,308 publications

(981 citation statements)

References 43 publications

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“…In fact, both its enzymatic activity and interaction with many target proteins makes PI 3-kinase a multifunctional enzyme that contributes to the pivotal role of PI 3-kinase signal transduction in controlling numerous cellular functions. PI3-kinase is the major regulator of neurotrophin-mediated survival in cortical, hippocampal, sensory, and motor neurons (Yao and Cooper, 1995;Skaper et al, 1998;Dolcet et al, 1999;Hetman et al, 1999;Liot et al, 2004), as well as glia (Rodgers and Theibert, 2002). One of the most important targets of PI 3-kinase is Akt (Vanhaesebroeck and Alessi, 2000;Patapoutian and Reichardt, 2001), which is activated after binding with the PI 3-kinase lipid product PI-3,4,5-P 3 or through phosphorylation by another target of PI 3-kinase, that is, PI-dependent kinase-1 (PDK-1) (Alessi et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we observed that expression of other neurotrophins, such as neurotrophin (NT)-3, NT-4/5, and NGF, is also abnormal in postmortem brain of suicide subjects (Dwivedi et al, 2005a). Since many physiological functions, including prosurvival effects of neurotrophins, occur through the activation of PI 3-kinase (Yao and Cooper, 1995;Crowder and Freeman, 1998;Hetman et al, 1999;Liot et al, 2004), it is important to examine whether this signaling system is altered in postmortem brain of suicide subjects and therefore plays any role in the pathophysiologic mechanisms of suicide. A recent study indicates that the catalytic activity of PI 3-kinase is decreased in occipital cortex of suicide subjects (Hsiung et al, 2003), which suggests the possible involvement of PI 3-kinase in suicide.…”

Section: Introductionmentioning

confidence: 99%

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Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Dwivedi

Rizavi

Teppen

et al. 2007

Neuropsychopharmacol

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Phosphoinositide 3 (PI 3)-kinase is one of the key signaling enzymes that participates in a myriad of physiological functions in brain and is utilized by neurotrophins to mediate neuronal plasticity, cell survival, and inhibition of apoptosis for several neuronal subtypes. Our recent demonstration that expression of neurotrophic factors and activation of the receptor tyrosine kinase B are significantly altered in postmortem brain of suicide subjects led us to examine whether suicide brain is associated with alterations in PI 3-kinase signaling. In prefrontal cortex (PFC), hippocampus, and cerebellum of suicide (n ¼ 28) and nonpsychiatric control (n ¼ 21) subjects we examined catalytic activation of PI 3-kinase, and mRNA and protein levels of regulatory (p85a, p85b) and catalytic (p110a, p110b) subunits of PI 3-kinase. It was observed that the catalytic activity of PI 3-kinase was significantly reduced in PFC and hippocampus of suicide subjects compared with nonpsychiatric control subjects. Competitive PCR analysis revealed significantly reduced mRNA expression of p85b and p110a and increased expression of p85a subunit isoforms in PFC and hippocampus of suicide subjects. Alterations in these catalytic and regulatory subunits were accompanied by changes in their respective protein levels. These changes were not present in cerebellum of suicide subjects. Also, these changes were present in all suicide subjects irrespective of psychiatric diagnosis. Our findings of reduced activation and altered expression of specific PI 3-kinase regulatory and catalytic subunit isoforms demonstrate abnormalities in this signaling pathway in postmortem brain of suicide subjects and suggest possible involvement of aberrant PI 3-kinase signaling in the pathogenic mechanisms of suicide.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Dwivedi

Rizavi

Teppen

et al. 2007

Neuropsychopharmacol

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“…NGF activates the PI3K/Akt pathway during PC12 cell differentiation 35 perhaps through Ras and Raf pathway. 19 Cdk5 knockout mice show inhibition of the PI3K/Akt pathway in neurons.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase-5 prevents neuronal apoptosis through ERK-mediated upregulation of Bcl-2

Wang

Song

et al. 2005

Cell Death Differ

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Cyclin-dependent kinase-5 (Cdk5) is required for neuronal survival, but its targets in the apoptotic pathways remain unknown. Here, we show that Cdk5 kinase activity prevents neuronal apoptosis through the upregulation of Bcl-2. Treatment of SH-SY5Y cells with retinoid acid (RA) and brain-derived neurotrophic factor (BDNF) generates differentiated neuron-like cells. DNA damage triggers apoptosis in the undifferentiated cells through mitochondrial pathway; however, RA/BDNF treatment results in Bcl-2 upregulation and inhibition of the mitochondrial pathway in the differentiated cells. RA/BDNF treatment activates Cdk5-mediated PI3K/Akt and ERK pathways. Inhibition of Cdk5 inhibits PI3K/ Akt and ERK phosphorylation and Bcl-2 expression, and thus sensitizes the differentiated cells to DNA-damage. Inhibition of ERK, but not PI3K/Akt, abrogates Cdk5-medidated Bcl-2 upregulation and the protection of the differentiated cells. This study suggests that ERK-mediated Bcl-2 upregulation contributes to BDNF-induced Cdk5-mediated neuronal survival.

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“…It has been demonstrated that cells with activated Akt/PKB pathway can withstand apoptotic stimuli [9]. The Akt/PKB can promote survival by regulating a number of transcription factors including forkhead transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Forkhead protein FKHR and its phosphorylated form p-FKHR in human prostate cancer

Erdamar

Dai

et al. 2007

Human Pathology

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SummaryIn vitro studies suggest that the proapoptotic function of forkhead protein FKHR is probably inactivated by means of phosphorylation through the protein kinase B pathway. However, the clinical significance of FKHR in prostate cancer remains unclear. Six hundred forty radical prostatectomies were used for building tissue microarrays. Slides were stained with antibodies against FKHR and phosphorylated FKHR (p-FKHR). Correlations with clinicopathologic parameters were analyzed by Spearman rank test. Cox regression test and Kaplan-Meier test were used to determine the probability of disease recurrence, which is defined as a serum prostate-specific antigen (PSA) level greater than 0.4 ng/mL after radical prostatectomy. Nuclear FKHR level was higher in normal prostate than in benign prostatic hyperplasia and prostate cancer (P = .0000). Nuclear expression of FKHR was correlated with preoperative PSA level (ρ = 0.108, P = .029), extracapsular extension (ρ = 0.137, P = .005), and seminal vesicle invasion (ρ = 0.101, P = .039). FKHR expression was not a significant indicator of biochemical failure by either univariate or multivariate analysis. Nuclear p-FKHR expression correlated with patients' age (ρ = 0.179, P = .0003), Gleason score (ρ = 0.130, P = .0083), extracapsular extension (ρ = 0.227, P = .0000), clinical stage (Union Internationale Contre le Cancer system) (ρ = 0.166, P = .0007), and lymph node status (ρ = 0.101, P = .0401). Cytoplasmic p-FKHR correlated with patients' age (ρ = 0.146, P = .0030) and clinical stage (ρ = 0.117, P = .0180). Cytoplasmic p-FKHR was a significant indicator of biochemical recurrence (P = .0164; hazard ratio, 1.114-2.929). Nuclear p-FKHR strongly correlated with phosphorylated protein kinase B (ρ = 0.368, P = .0000), androgen receptor (ρ = 0.385, P = .0000), and Skp-2 (ρ = 0.170, P = .0036). Our data suggest that the proapoptotic role of FKHR is probably regulated by several signaling pathways in prostate cancer.

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Requirement for Phosphatidylinositol-3 Kinase in the Prevention of Apoptosis by Nerve Growth Factor

Cited by 1,308 publications

References 43 publications

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Cyclin-dependent kinase-5 prevents neuronal apoptosis through ERK-mediated upregulation of Bcl-2

Forkhead protein FKHR and its phosphorylated form p-FKHR in human prostate cancer

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