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MTOR NDRG1 (1 - 2 of 2)
PMID: 15545625
Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.
... that mTOR inhibition ... hypoxia requires the ... gene REDD1/RTP801.   (details)

MTOR NDRG1

Type:  negative regulation
Is this interaction correct?
Yes
No

Comments

PMID: 15545625

Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.
Source

Genes & development (12/1/2004)

Abstract

Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801. Disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 blocks the effects of hypoxia on mTOR, as measured by changes in the mTOR targets S6K and 4E-BP1, and results in abnormal accumulation of Hypoxia-inducible factor (HIF). In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1. Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene. Disruption of REDD1 abrogates the hypoxia-induced inhibition of mTOR, and REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia.

PMID: 19507250
Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells.
... of RTP801, ... and inhibited mTORC1 signaling ...   (details)

MTOR NDRG1

Type:  negative regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 19507250

Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells.
Source

International journal of cancer. Journal international du cancer (10/1/2009)

Abstract

Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells. Our study explored the drug interaction of all-trans retinoic acid (ATRA) and RAD001 (everolimus), the inhibitor of mammalian target of rapamycin complex 1 (mTORC1), in acute myelogenous leukemia (AML) NB4 and HL60 cells. RAD001 (10 nM) significantly enhanced the ATRA-induced growth arrest and differentiation of these cells, as measured by colony-forming assay and cell cycle analysis, and expression of CD11b cell surface antigen and nitroblue tetrazolium reduction, respectively. ATRA (0.1-1 microM) upregulated levels of RTP801, a negative regulator of mTORC1, and inhibited mTORC1 signaling as assessed by measurement of the levels of p-p70S6K and p-4E-BP1 in HL60 and NB4 cells. ATRA (0.1-1 microM) in combination with RAD001 (10 nM) strikingly downregulated the levels of p-70S6K and p-4E-BP1 without affecting the total amount of these proteins. Notably, RAD001 (10 nM) significantly augmented ATRA-induced expression of CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) and p27 (kip1) and downregulated levels of c-Myc in these cells. Furthermore, RAD001 (5 mg/kg) enhanced the ability of ATRA (10 mg/kg) to inhibit the proliferation of HL60 cells growing as tumor xenografts in immune-deficient nude mice. Taken together, concomitant blockade of the RA and mTORC1 signaling may be a promising treatment strategy for individuals with AML.