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MTOR MDM2 (1 - 3 of 3)
PMID: 15199126
Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53.
... in MDM2 expression ... were blocked by ... of mTOR and ...   (details)

MTOR MDM2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 15199126

Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53.
Source

Molecular and cellular biology (July 2004)

Abstract

Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53. Phospholipase D (PLD) has been reported to generate survival signals that prevent apoptosis induced by serum withdrawal. We have now found that elevated expression of PLD also suppresses DNA damage-induced apoptosis. Since DNA damage-induced apoptosis is often mediated by p53, we examined the effect of elevated PLD expression on the regulation of p53 stabilization. We report here that PLD suppresses DNA damage-induced increases in p53 stabilization in cells where PLD has been shown to provide a survival signal. Elevated expression of PLD also led to increased expression of the p53 E3 ubiquitin ligase MDM2 and increased turnover of p53. PLD1-stimulated increases in MDM2 expression and suppression of p53 activation were blocked by inhibition of mTOR and the mitogen-activated protein kinase pathway. Although PLD did not activate the phosphatidylinositol 3-kinase (PI3K) /Akt survival pathway activate the basal levels of PI3K activity were partially required for PLD1-induced increases in MDM2. These data provide evidence that survival signals generated by PLD involve suppression of the p53 response pathway.

PMID: 15625077
HMG-CoA reductase inhibitors, statins, induce phosphorylation of Mdm2 and attenuate the p53 response to DNA damage.
... an mTOR-dependent Ser166 ... of Mdm2, ...   (details)

MTOR MDM2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 15625077

HMG-CoA reductase inhibitors, statins, induce phosphorylation of Mdm2 and attenuate the p53 response to DNA damage.
Source

FASEB journal : official publication of the Federation of American Societies for Experimental Biology (March 2005)

Abstract

HMG-CoA reductase inhibitors, statins, induce phosphorylation of Mdm2 and attenuate the p53 response to DNA damage. 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, statins, are widely used cholesterol-lowering drugs and have been shown to have anticancer effects in many models. We have investigated the effect of statins on Mdm2, a p53-specific ubiquitin ligase. It was found that pravastatin induced Mdm2 phosphorylation at Ser166 and at 2A10 antibody-specific epitopes in HepG2 cells, while mRNA levels were unchanged. Furthermore, pravastatin was found to induce phosphorylation of mTOR at Ser2448. Ser166 phosphorylation of Mdm2 was abrogated by an inhibitor of mTOR, rapamycin, but not by the PI3-kinase inhibitors LY294002 and wortmannin. Ser166 phosphorylation of Mdm2 has been associated to active Mdm2 and has been shown to increase its ubiquitin ligase activity and lead to increased p53 degradation. Our data show that statins attenuated the p53 response to DNA damage. Thus, in HepG2 cells pravastatin and simvastatin pretreatment attenuated the p53 response to DNA damage induced by 5-fluorouracil and benzo (a) pyrene. Similar attenuation was induced when p53 stabilization was induced by the inhibitor of nuclear export, leptomycin B. Furthermore, in the DNA-damaged cells, half-lives of Mdm2 and p53 were decreased by statins, indicating a more rapid formation of p53/Mdm2 complexes and facilitated p53 degradation. The induction of p53 responsive genes and apoptosis was attenuated. Mdm2 and p53 were also studied in vivo in rat liver employing immunohistochemistry, and it was found that constitutive Mdm2 expression was changed in livers of pravastatin-treated rats. We also show that the p53 response to a challenging dose of diethylnitrosamine was attenuated in hepatocytes in situ and in primary cultures of hepatocytes by pravastatin pretreatment. Taken together, these data indicate that statins induce an mTOR-dependent Ser166 phosphorylation of Mdm2, and this effect may attenuate the duration and intensity of the p53 response to DNA damage in hepatocytes.

PMID: 20438709
Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway.
... of HDM2 involves mTORC2 and ...   (details)

MTOR MDM2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )

PMID: 20438709

Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway.
Source

Biochemical and biophysical research communications (5/28/2010)

Abstract

Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway. Phosphatidic acid (PA), the primary metabolite of the phospholipase D (PLD) -mediated hydrolysis of phosphatidylcholine, has been shown to act as a tumor promoting second messenger in many cancer cell lines. A key target of PA is the mammalian target of rapamycin (mTOR), a serine-threonine kinase that has been widely implicated in cancer cell survival signals. In agreement with its ability to relay survival signals, it has been reported that both PLD and mTOR are required for the stabilization of the p53 E3 ubiquitin ligase human double minute 2 (HDM2) protein. Thus, by stabilizing HDM2, PLD and mTOR are able to counter the pro-apoptotic signaling mediated by p53 and promote survival. mTOR exists in at least two distinct complexes-mTORC1 and mTORC2-that are both dependent on PLD-generated PA. Although PLD and its metabolite PA are clearly implicated in the transduction of survival signals to mTOR, it is not yet apparent which of the two mTOR complexes is critical for the stabilization of HDM2. We report here that the PLD/mTOR-dependent stabilization of HDM2 involves mTORC2 and the AGC family kinase serum- and glucocorticoid-inducible kinase 1 (SGK1). This study reveals that mTORC2 is a critical target of PLD-mediated survival signals and identifies SGK1 as a downstream target of mTORC2 for the stabilization of HDM2.