Phosphatidylinositol 3-kinase is essential for the proliferation of lymphoblastoid cells

Brennan, Paul; Mehl, Anja; Jones, Matt; Rowe, Martin

doi:10.1038/sj.onc.1205182

Cited by 52 publications

(53 citation statements)

References 59 publications

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“…How does PI3-kinase inhibition induce growth retardation if ES cells lack cyclin D : CDK4-associated kinase activity? First, PI3-kinase signalling is known to be involved in the regulation of p27 kip1 kinase inhibitor (Li and Sun, 1998;Dijkers et al, 2000;Murillo et al, 2001;Brennan et al, 2002). ES cells lacking the PTEN function display reduced p27 kip1 level and shortened cell cycle (Sun et al, 1999).…”

Section: Pi3-kinase Signalling Plays a Critical Role In The G1/s Tranmentioning

confidence: 99%

“…Thus, the PI3-kinase-dependent signalling pathway up-regulates cyclin D1 translation and down-regulates cyclin D1 degradation, both in response to mitogenic stimuli. PI3-kinase-dependent signalling is also known to regulate the level of p27 kip1 , a major inhibitor of G1 CDKs (Sherr and Roberts, 1999;Sun et al, 1999;Dijkers et al, 2000;Murillo et al, 2001;Brennan et al, 2002). By virtue of their regulation by Ras and/or PI3-kinase activities, the expression levels of cyclin D1 and of p27 kip1 are directly responsive to the extracellular growth factor environment.…”

Section: Introductionmentioning

confidence: 99%

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Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells

et al. 2002

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Mouse embryonic stem (ES) cells are known to express D-type cyclins at very low levels and these levels increase dramatically during in vitro and in vivo differentiation. Here, we investigate some of the signalling pathways regulating expression of cyclin D1 and progression to S phase, the Ras/Extracellular signal-regulated protein kinase (ERK) pathway and the phosphatidylinositol 3-kinase (PI3-kinase) pathway. We demonstrate that ERK phosphorylation is fully dispensable for the regulation of cyclin D1 level and for the progression from G1 to S phase in ES cells. By contrast, PI3-kinase activity is required for both. Differentiation induced by retinoic acid results in the gain of ERK-dependent control of cyclin D1 expression and of S phase progression. Differentiation is also paralleled by an increase in PI3-kinase activity. This leads (a) to an increase in the p70 S6 kinase-dependent regulation of the steady-state level of cyclin D1, and (b) to a concomitant decrease in the GSK3b-dependent rate of cyclin D1 degradation. Altogether, these multiple pathways account for the dramatic increase in the level of cyclin D1 protein which parallels ES cell differentiation. Our studies suggest that PI3-kinase is an important regulator of the ES cell cycle and that its activity is not regulated by mitogen stimulation.

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Section: Pi3-kinase Signalling Plays a Critical Role In The G1/s Tranmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells

et al. 2002

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“…1,2 A signaling pathway of great importance in the regulation of cell-cycle progression, proliferation and apoptosis is the phosphatidylinositol-3 kinase (PI3K)-Akt network. 3 Indeed, over the last few years many studies have provided convincing evidence that constitutive activation of this signaling network is involved in the aggressiveness and resistance to therapeutic treatments of a large number of malignant diseases. [4][5][6] Accordingly, the dysregulated activation of the PI3K-Akt survival pathway is often associated with hematological malignancies, including acute and chronic human leukemias.…”

Section: Introductionmentioning

confidence: 99%

“…Once activated by different growth factors and cytokines, PI3K localizes to the plasma membrane and catalyzes the g-phosphate transfer of ATP to the D3 position of phosphoinositides, thereby producing phosphatidylinositol [3][4][5] triphosphate (PIP 3 ), which in turn activates a number of critical downstream substrates, including the serine/threonine kinase Akt. Akt recruitment to the plasma membrane provides conformational changes, which enable the phosphorylation of both the catalytic loop at Thr 308 and the C-terminal hydrophobic tail at Ser 473.…”

Section: Introductionmentioning

confidence: 99%

Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells

et al. 2007

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The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myelogenous leukemia (AML). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine, on human AML cells. Perifosine is a synthetic alkylphospholipid, a new class of antitumor agents, which target plasma membrane and inhibit signal transduction networks. Perifosine was tested on THP-1 and MV 4-11 cell lines, as well as primary leukemia cells. Perifosine treatment induced cell death by apoptosis in AML cell lines. Perifosine caused Akt and ERK 1/2 dephosphorylation as well as caspase activation. In THP-1 cells, the proapoptotic effect of perifosine was partly dependent on the Fas/FasL system and c-jun-N-kinase activation. In MV 4-11 cells, perifosine downregulated phosphorylated Akt, but not phosphorylated FLT3. Moreover, perifosine reduced the clonogenic activity of AML, but not normal, CD34 þ cells, and markedly increased blast cell sensitivity to etoposide. Our findings indicate that perifosine, either alone or in combination with existing drugs, might be a promising therapeutic agent for the treatment of those AML cases characterized by upregulation of the PI3K-Akt survival pathway.

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“…Activation of the pathway results in the constitutive delivery of an antiapoptotic signal. Akt is also involved in the control of B-cell proliferation because chemical inhibition of PI3-K induced growth arrest of EBV-transformed B cells (Brennan et al, 2002).…”

Section: Latent Membrane Proteinmentioning

confidence: 99%

The Viral Etiology of AIDS‐Associated Malignancies

Angeletti

Zhang

Wood

2008

Advances in Pharmacology

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Phosphatidylinositol 3-kinase is essential for the proliferation of lymphoblastoid cells

Cited by 52 publications

References 59 publications

Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells

Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells

Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells

The Viral Etiology of AIDS‐Associated Malignancies

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