Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

@article{Lacher2010RhebAA,
  title={Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis},
  author={Markus D. Lacher and Roxana Pincheira and Z. Zhu and Blanca Camoretti-Mercado and Mary R Matli and R Warren and A F Castro},
  journal={Oncogene},
  year={2010},
  volume={29},
  pages={6543-6556}
}
Tuberous sclerosis complex (TSC) is an autosomally inherited disorder that causes tumors to form in many organs. It is frequently caused by inactivating mutations in the TSC2 tumor-suppressor gene. TSC2 negatively regulates the activity of the GTPase Rheb and thereby inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling. Activation of mTORC1 as a result of lack of TSC2 function is observed in TSC and sporadic lymphangioleiomyomatosis (LAM). TSC2 deficiency has recently been… 
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40 Citations

Consequences of interrupted Rheb-to-AMPK feedback signaling in tuberous sclerosis complex and cancer
TLDR
How Rheb-to-AMPK, and p27 signaling may impact on disease progression and treatment of TSC, including sporadic lymphangioleio-myomatosis (S-LAM) and malignancies is discussed.
Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survival.
TSC-insensitive Rheb mutations induce oncogenic transformation through a combination of constitutively active mTORC1 signalling and proteome remodelling.
TLDR
It is shown that a number of recurrently occurring Rheb mutants drive hyperactive mTORC1 signalling through differing levels of insensitivity to the primary inactivator of RheB, tuberous sclerosis complex, which suggests that unique, personalized, combination therapies may be utilised to treat cancers according to which Rhe b mutant they harbour.
Tuberin Regulates Prostaglandin Receptor–Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells
TLDR
Upregulation of EP3 (PTGER3) expression in TSC2-deficient cells, TSC renal angiomyolipomas, lymphangioleiomyomatosis lung nodules, and epileptic brain tubers is identified.
Inhibition of MAPK pathway is essential for suppressing Rheb-Y35N driven tumor growth
TLDR
It is shown that Rheb-Y35N causes not only constitutive mTORC1 activation, but sustained activation of the MEK-ERK pathway in a TSC1/TSC2/TBC1D7 protein complex and m TORC1-independent manner, contributing to intrinsic resistance to rapamycin.
mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy
TLDR
The results suggest that autophagy via the TSC2-mTORC1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart and could be a therapeutic target to maintain mitochondrial homeostasis in failing hearts.
Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival of Tsc2-Null Cells
TLDR
The pharmacological PDEδ inhibition is proposed as a new approach to target the abnormal Rheb/mTORC1 activation in Tuberous Sclerosis Complex cells.
Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia
TLDR
The data suggest that Rheb1 promotes AML progression through mTORC1 signaling pathway and combinational drug treatments targeting RheB1 and mTOR might have a better therapeutic effect on leukemia.
Loss of TSC2 confers resistance to ceramide and nutrient deprivation
TLDR
Results suggest that, in the absence of oncogene-driven biosynthetic demand, mTORC1-dependent translation facilitates the adaptive cellular response to nutrient stress.
Depletion of p18/LAMTOR1 promotes cell survival via activation of p27kip1‐dependent autophagy under starvation
TLDR
The data suggest that ablation of p18/LAMTOR1 suppresses starvation‐induced cell death by stimulating autophagy through modulation of p27kip1 activity.
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References

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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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