The life of a cell: apoptosis regulation by the PI3K/PKB pathway

Duronio, Vincent

doi:10.1042/bj20081056

Cited by 334 publications

(266 citation statements)

References 179 publications

(181 reference statements)

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“…AKT is known to block apoptotic pathways (Nicholson and Anderson, 2002;Duronio, 2008). In addition to AKT, apoptosis was increased by cyclin D1 siRNA in long-term FR cells.…”

Section: Discussionmentioning

confidence: 98%

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

et al. 2010

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Recurrence is frequently associated with the acquisition of radioresistance by tumors and resulting failures in radiotherapy. We report, in this study, that long-term fractionated radiation (FR) exposures conferred radioresistance to the human tumor cells, HepG2 and HeLa with cyclin D1 overexpression. A positive feedback loop was responsible for the cyclin D1 overexpression in which constitutively active AKT was involved. AKT is known to inactivate glycogen synthase kinase-3b (GSK3b), which is essential for the proteasomal degradation of cyclin D1. The resulting cyclin D1 overexpression led to the forced progression of S-phase with the induction of DNA double strand breaks. Cyclin D1-dependent DNA damage activated DNA-dependent protein kinase (DNA-PK), which in turn activated AKT and inactivated GSK3b, thus completing a positive feedback loop of cyclin D1 overproduction. Cyclin D1 overexpression led to the activation of DNA damage response (DDR) consisted of ataxia telangiectasia mutated (ATM)-and Chk1-dependent DNA damage checkpoint and homologous recombination repair (HRR). Long-term FR cells repaired radiation-induced DNA damage faster than non-FR cells. Thus, acquired radioresistance of long-term FR cells was the result of alterations in DDR mediated by cyclin D1 overexpression. Inhibition of the AKT/GSK3b/cyclin D1/ Cdk4 pathway by the AKT inhibitor, Cdk4 inhibitor or cyclin D1 targeting small interfering RNA (siRNA) suppressed the radioresistance. Present observations give a mechanistic insight for acquired radioresistance of tumor cells by cyclin D1 overexpression, and provide novel therapeutic targets for recurrent radioresistant tumors.

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“…AKT is known to block apoptotic pathways (Nicholson and Anderson, 2002;Duronio, 2008). In addition to AKT, apoptosis was increased by cyclin D1 siRNA in long-term FR cells.…”

Section: Discussionmentioning

confidence: 98%

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

et al. 2010

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“…Furthermore, we show that inhibition of PKB with triciribine causes ISO to behave as an inverse agonist, leading to the inhibition of RNA synthesis, as opposed to its previously noted stimulatory effect. At the level of the plasma membrane, PI3K activation leads to the recruitment of phosphoinositide-dependent kinase-1 (PDK1) and PKB via their pleckstrin homology (PH) domains, where PDK1 is able to phosphorylate PKB at threonine 308 and thereby activate it [30]. Once activated, PKB can accumulate both in the cytoplasm and the nucleus [11,31,32].…”

Section: Discussionmentioning

confidence: 99%

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

Vaniotis

Duca

Trieu

et al. 2011

Cellular Signalling

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Both β 1 -and β 3 -adrenergic receptors (β 1 ARs and β 3 ARs) are present on nuclear membranes in adult ventricular myocytes. These nuclear-localized receptors are functional with respect to ligand binding and effector activation. In isolated cardiac nuclei, the non-selective βAR agonist isoproterenol stimulated de novo RNA synthesis measured using assays of transcription initiation (Boivin et al., 2006 Cardiovasc Res. 71:69-78). In contrast, stimulation of endothelin receptors, another G protein-coupled receptor (GPCR) that localizes to the nuclear membrane, resulted in decreased RNA synthesis. To investigate the signalling pathway(s) involved in GPCR-mediated regulation of RNA synthesis, nuclei were isolated from intact adult rat hearts and treated with receptor agonists in the presence or absence of inhibitors of different mitogen-activated protein kinase (MAPK) and PI3K/PKB pathways. Components of p38, JNK, and ERK1/2 MAP kinase cascades as well as PKB were detected in nuclear preparations. Inhibition of PKB with triciribine, in the presence of isoproterenol, converted the activation of the βAR from stimulatory to inhibitory with regards to RNA synthesis, while ERK1/2, JNK and p38 inhibition reduced both basal and isoproterenol-stimulated activity. Analysis by qPCR indicated an increase in the expression of 18 S rRNA following isoproterenol treatment and a decrease in NFκB mRNA. Further qPCR experiments revealed that isoproterenol treatment also reduced the expression of several other genes involved in the activation of NFκB, while ERK1/2 and PKB inhibition substantially * Corresponding authors. Hébert is to be contacted

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“…Altered PI3K pathway activity appears to contribute to the regulation of many different cellular processes but is most consistently associated with the control of cell proliferation, growth, survival, metabolic reprogramming, motility and polarity [2,[13][14][15]. These effects are mediated through a large and diverse group of proteins that can bind selectively to the PtdInsP 3 lipid, the best studied of which are the AKT kinases [2].…”

Section: Introductionmentioning

confidence: 99%

Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110α/PIK3CA but not by HER2 or mutant AKT1

et al. 2012

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Genetic changes in HER2, PTEN, PIK3CA and AKT1 are all common in breast cancer and lead to the elevated phosphorylation of downstream targets of the PI3K/AKT signalling pathway. Changes in HER2, PTEN, PIK3CA and AKT have all been reported to lead to both enhanced proliferation and failures in hollow lumen formation in three dimensional epithelial culture models, but it is not clear whether these failures in lumen formation are caused by any failure in the spatial coordination of lumen formation (hollowing) or purely a failure in the apoptosis and clearance of luminal cells (cavitation). Here we use NMuMG mammary epithelial cells, which form a hollow lumen without significant apoptosis, to compare the transformation by these four genetic changes. We find that either mutant PIK3CA expression or PTEN loss, but not mutant AKT1 E17K, cause disrupted epithelial architecture, whereas HER2 over-expression drives strong proliferation without affecting lumen formation in these cells. We also show that PTEN requires both lipid and protein phosphatase activity, its extreme C-terminal PDZ binding sequence and probably Myosin 5A to control lumen formation through a mechanism that does not correlate with its ability to control AKT, but which is selectively lost through mutation in some tumours. These findings correlate AKT independent signalling activated by mutant PIK3CA or PTEN loss, but not strongly by HER2, with disrupted epithelial architecture and tumour formation.

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The life of a cell: apoptosis regulation by the PI3K/PKB pathway

Cited by 334 publications

References 179 publications

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110α/PIK3CA but not by HER2 or mutant AKT1

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