Dysregulation of the TSC-mTOR pathway in human disease

Inoki, Ken; Corradetti, Michael N.; Guan, Kun Liang

doi:10.1038/ng1494

Cited by 910 publications

(777 citation statements)

References 94 publications

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“…34 At present, it is not clear whether the activation of mTOR by amino acids is direct, whether it involves the inhibition of tuberous sclerosis complex (TSC)1/2 (which inhibits mTOR), or whether the activation of mTOR occurs via decreased Ras homolog enriched in brain (Rheb) GTPase activity. 35 Recent evidence indicates that it is unlikely that the inhibition of TSC2 by amino acids is the mechanism involved. 36 The idea that mTOR is involved in the negative control of autophagy is now generally accepted, 13 but the mechanism by which this occurs is still largely unknown.…”

Section: Inhibition Of Autophagy By Amino Acidsmentioning

confidence: 99%

Autophagy and signaling: their role in cell survival and cell death

2005

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Macroautophagy is a vacuolar, self-digesting mechanism responsible for the removal of long-lived proteins and damaged organelles by the lysosome. The discovery of the ATG genes has provided key information about the formation of the autophagosome, and about the role of macroautophagy in allowing cells to survive during nutrient depletion and/or in the absence of growth factors. Two connected signaling pathways encompassing class-I phosphatidylinositol 3-kinase and (mammalian) target of rapamycin play a central role in controlling macroautophagy in response to starvation. However, a considerable body of literature reports that macroautophagy is also a cell death mechanism that can occur either in the absence of detectable signs of apoptosis (via autophagic cell death) or concomitantly with apoptosis. Macroautophagy is activated by signaling pathways that also control apoptosis. The aim of this review is to discuss the signaling pathways that control macroautophagy during cell survival and cell death.

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Section: Inhibition Of Autophagy By Amino Acidsmentioning

confidence: 99%

Autophagy and signaling: their role in cell survival and cell death

2005

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“…In PTEN deficient mouse, the PI3K pathway is constitutively activated, which in turn activates the mammalian target of rapamycin (mTOR). The drug rapamycin inhibits mTOR kinase activity [87][88][89] .…”

Section: Disruption Of Critical Self-renewal Pathwaysmentioning

confidence: 99%

“…PTEN deficiency activates PI3K pathway, which in turn activates mTOR. Rapamycin is an active drug that inhibits mTOR kinase activity, and patients with acute leukemia respond to this drug 87,88 . In the PTEN-deficient mice, rapamycin successfully eradicated leukemia by depleting leukemiainitiating cells and rescuing the capacity of normal HSCs to provide long-term multilineage reconstitution.…”

Section: Cancer Stem Cells From a Therapeutic Perspectivementioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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“…One downstream molecule of mammalian target of rapamycin (mTOR) is ribosomal S6 kinase (p70S6K). This kinase regulates the efficiency of translation of certain mRNAs and also functions in a negative feedback loop to control Akt activity (Chiang and Abraham, 2005;Inoki et al, 2005;Martelli et al, 2007). Akt, mTOR and p70S6K activation have been associated with a more severe prognosis in breast and other cancers (Bose et al, 2002;Clark et al, 2002;DeGraffenried et al, 2004;Nagata et al, 2004;Lin et al, 2005;Tsutsui et al, 2005a, b;Klos et al, 2006;Tokunaga et al, 2006;Martelli et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors

et al. 2008

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Ectopic expression of mutant forms of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) lacking lipid (G129E) or lipid and protein (C124S) phosphatase activity decreased sensitivity of MCF-7 breast cancer cells, which have wild-type PTEN, to doxorubicin and increased sensitivity to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. Cells transfected with a mutant PTEN gene lacking both lipid and protein phosphatase activities were more resistant to doxorubicin than cells transfected with the PTEN mutant lacking lipid phosphatase activity indicating that the protein phosphatase activity of PTEN was also important in controlling the sensitivity to doxorubicin, while no difference was observed between the lipid (G129E) and lipid and protein (C124S) phosphatase PTEN mutants in terms of sensitivity to rapamycin. A synergistic inhibitory interaction was observed when doxorubicin was combined with rapamycin in the phosphatase-deficient PTENtransfected cells. Interference with the lipid phosphatase activity of PTEN was sufficient to activate Akt/mTOR/ p70S6K signaling. These studies indicate that disruption of the normal activity of the PTEN phosphatase can have dramatic effects on the therapeutic sensitivity of breast cancer cells. Mutations in the key residues which control PTEN lipid and protein phosphatase may act as dominant-negative mutants to suppress endogenous PTEN and alter the sensitivity of breast cancer patients to chemo-and targeted therapies.

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Dysregulation of the TSC-mTOR pathway in human disease

Cited by 910 publications

References 94 publications

Autophagy and signaling: their role in cell survival and cell death

Autophagy and signaling: their role in cell survival and cell death

Somatic stem cells and the origin of cancer

Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors

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