Phosphoinositide 3-kinase signalling – which way to target?

Wymann, Matthias P.; Zvelebil, Marketa; Laffargue, Muriel

doi:10.1016/s0165-6147(03)00163-9

Cited by 374 publications

(292 citation statements)

References 85 publications

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“…PI3Ks play a key role in the control of cell growth, proliferation, survival and migration [12] . It was reported that the adenoviral gene transfer of activated phosphatidylinositol 3'-kinase and Akt inhibited the apoptosis of hypoxic cardiomyocytes in vitro [24] .…”

Section: Discussionmentioning

confidence: 99%

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The PI3K/Akt pathway mediates the protection of SO2 preconditioning against myocardial ischemia/reperfusion injury in rats

Zhao¹,

Yang²,

Wang³

et al. 2013

Acta Pharmacol Sin

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Aim: To explore the mechanisms underlying the protection by SO 2 preconditioning against rat myocardial ischemia/reperfusion (I/R) injury. Methods: Male Wistar rats underwent 30-min left coronary artery ligation followed by 120-min reperfusion. An SO 2 donor (1 μmol/kg) was intravenously injected 10 min before the ischemia, while LY294002 (0.3 mg/kg) was intravenously injected 30 min before the ischemia. Plasma activities of LDH and CK were measured with an automatic enzyme analyzer. Myocardial infarct size was detected using Evans-TTC method. The activities of caspase-3 and -9 in myocardium were assayed using a commercial kit, and the levels of p-Akt, Akt, PI3K and p-PI3K were examined with Western blotting. Results: Pretreatment with SO 2 significantly reduced the myocardial infarct size and plasma LDH and CK activities, as well as myocardial caspase-3 and -9 activities in the rats. Furthermore, the pretreatment significantly increased the expression levels of myocardial p-Akt and p-PI3K p85. Administration of the PI3K inhibitor LY294002 blocked all the effects induced by SO 2 pretreatment. Conclusion:The results suggest that the PI3K/Akt pathway mediates the protective effects of SO 2 preconditioning against myocardial I/R injury in rats.

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Section: Discussionmentioning

confidence: 99%

“…PI3Ks play an important role in the control of cell growth, proliferation, survival and migration [12] . The activation of Akt, which is downstream of PI3K, may ameliorate I/R injury [13] .…”

Section: Introductionmentioning

confidence: 99%

The PI3K/Akt pathway mediates the protection of SO2 preconditioning against myocardial ischemia/reperfusion injury in rats

Zhao¹,

Yang²,

Wang³

et al. 2013

Acta Pharmacol Sin

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“…PI 3-kinases are a subfamily of lipid kinases that phosphorylate the three-dimensional position of the inositol ring of PI generating second messengers that are involved in many physiological functions, including cell proliferation, cell survival, cell morphology, synaptic plasticity, protein synthesis, and membrane trafficking (Lin et al, 2001;Cantley, 2002;Rodgers and Theibert, 2002;Wymann et al, 2003;Downes et al, 2005;Downward, 2004;Engelman et al, 2006). PI 3-kinase proteins have been divided into three classes that differ in structure, substrate specificity, tissue distribution, and in functions.…”

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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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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“…Phosphatidyl-inositol 3-kinase (PI3 K), which relays various signalling pathways via the production of phosphatidyl-inositide lipids, has been identified as a central mediator of cell growth, metabolism, migration, and survival (reviewed in Wymann et al, 2003). PI3 K regulates cellular functions by recruiting PI(3, 4, 5)P 3 binding proteins to the plasma membrane preferentially via pH domains.…”

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confidence: 99%

Molecular alterations in apoptotic pathways after PKB/Akt-mediated chemoresistance in NCI H460 cells

Hövelmann¹,

Beckers

Schmidt³

2004

Br J Cancer

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Protein kinase B/Akt has been described as a central mediator of antiapoptotic signals in cancer cells. Furthermore, Akt has been shown to affect cell cycle progression and proliferative pathways and to possess a potential function in tumorigenesis and chemoresistance. In this study, we show that the ectopic expression of a constitutively active form of Akt1 (CA-Akt1) results in enhanced chemoresistance of NCI H460 human NSCLC cells towards a panel of chemotherapeutic agents. To understand the molecular alterations leading to impaired chemosensitivity mediated by activated Akt, we analysed various apoptotic pathways, including the activation of p53, caspases 3, 7, 8, and 9, release of cytochrome c from mitochondria, and the expression levels of proand antiapoptotic proteins such as Bcl-2, Bcl-x L , Bcl-x s , Bax, or Bfl-1. We observed that expression of CA-Akt did not interfere with single defined apoptotic switches, but modulated the apoptotic threshold of several apoptotic pathways towards increasing the threshold of onset. In particular, we found that CA-Akt-expressing cells displayed increased expression of the antiapoptotic Bcl-2 family member protein Bcl-x l , and a delayed onset of the p53 pathway after treatment with cisplatin or Mitoxantrone. Thus, our data suggest that Akt mediates chemoresistance in NHI H460 cells by interfering with and delaying the onset of various apoptotic pathways. A complete inactivation of apoptotic pathways was observed in none of the molecular alterations investigated. Our data strengthen the role of Akt as a central mediator of cell survival signals and/or chemoresistance and as an attractive target for cancer cell chemosensitisation.

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Phosphoinositide 3-kinase signalling – which way to target?

Cited by 374 publications

References 85 publications

The PI3K/Akt pathway mediates the protection of SO2 preconditioning against myocardial ischemia/reperfusion injury in rats

The PI3K/Akt pathway mediates the protection of SO2 preconditioning against myocardial ischemia/reperfusion injury in rats

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

Molecular alterations in apoptotic pathways after PKB/Akt-mediated chemoresistance in NCI H460 cells

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