Efficacy of a rapamycin analog (CCI‐779) and IFN‐γ in tuberous sclerosis mouse models

Lee, Laifong; Sudentas, Paul; Donohue, Brian; Asrican, Kirsten; Worku, Aelaf; Walker, Victoria; Sun, Yanping; Schmidt, Karl F.; Albert, Mitchell S.; El-Hashemite, Nisreen; Lader, Alan S.; Onda, Hiroaki; Zhang, Hongbing; Kwiatkowski, David J.; Dabora, Sandra L.

doi:10.1002/gcc.20118

Cited by 159 publications

(138 citation statements)

References 38 publications

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“…However, in animal models and clinical trials, rapamycin, which is intended to block cell growth and proliferation, only partially inhibits tumor or disease progression (44,45), suggesting that alternative signaling mechanisms might be targeted. In fact, tuberous sclerosis complex 2-deficient tumors are particularly sensitive to the growth inhibitory effects of IFN-␥ and exhibit dysregulated STAT1 signaling (46).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Mammalian Target of Rapamycin Increases STAT1 Nuclear Content and Transcriptional Activity in α4- and Protein Phosphatase 2A-dependent Fashion

Fielhaber¹,

Han²,

Tan

et al. 2009

Journal of Biological Chemistry

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Target of rapamycin (TOR) is a highly conserved serine/threonine kinase that controls cell growth, primarily via regulation of protein synthesis. In Saccharomyces cerevisiae, TOR can also suppress the transcription of stress response genes by a mechanism involving Tap42, a serine/threonine phosphatase subunit, and the transcription factor Msn2. A physical association between mammalian TOR (mTOR) and the transcription factor signal transducer and activator of transcription-1 (STAT1) was recently identified in human cells, suggesting a similar role for mTOR in the transcription of interferon-␥-stimulated genes. In the current study, we identified a macromolecular protein complex composed of mTOR, STAT1, the Tap42 homologue ␣4, and the protein phosphatase 2A catalytic subunit (PP2Ac). Inactivation of mTOR enhanced its association with STAT1 and increased STAT1 nuclear content in PP2Ac-dependent fashion. Depletion of ␣4, PP2A, or mTOR enhanced the induction of early (i.e. IRF-1) and late (i.e. caspase-1, hiNOS, and Fas) STAT1-dependent genes. The regulation of IRF-1 or caspase-1 by mTOR was independent of other known mTOR effectors p70 S6 kinase and Akt. These results describe a new role for mTOR and ␣4/PP2A in the control of STAT1 nuclear content, and the expression of interferon-␥-sensitive genes involved in immunity and apoptosis.The macrocyclic lactone rapamycin (Sirolimus, Rapamune TM ), as well as its analogues temsirolimus (CCI-779, Torisel TM ) and everolimus (RAD-001, Certican TM ), are approved for immunosuppression after organ transplantation, treatment of renal cell carcinoma, and the prevention of coronary artery in-stent restenosis (1). Their only known target is mammalian target of rapamycin (mTOR), 3 a highly conserved protein that controls cell growth in response to mitogens and changes in cellular metabolism. The effects of mTOR on cell growth involve the phosphorylation of p70 S6 kinase (S6K) and the translation inhibitor 4E-BP1, key regulators of ribosomal biogenesis and the initiation of protein synthesis (2). In contrast to its role in the initiation of translation, the current study focuses on mTOR as a regulator of mammalian gene transcription. Studies in Saccharomyces cerevisiae have revealed possible mechanisms by which mTOR might control mammalian transcription factors. TOR-regulated transcriptional control pathways include ribosomal biogenesis, the nutrient deprivation response, and the stress response (3). TOR stimulates 35 S ribosomal RNA expression and ribosomal biogenesis in nutrientdependent fashion. Inhibition of TOR (e.g. rapamycin or amino acid depletion) reproduces a catabolic response in part by inhibiting rRNA synthesis. In the nutrient deprivation and stress responses, TOR controls the nuclear localization of key transcription factors by mechanisms that require its associated serine/threonine phosphatases (i.e. Pph21, Pph22, or Sit4) and their adaptor, Tap42 (3). Rapamycin blocks phosphorylation of the transcription factor Gln3, as well as its cytosolic scaffolding protein Ure...

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Section: Discussionmentioning

confidence: 99%

Inactivation of Mammalian Target of Rapamycin Increases STAT1 Nuclear Content and Transcriptional Activity in α4- and Protein Phosphatase 2A-dependent Fashion

Fielhaber¹,

Han²,

Tan

et al. 2009

Journal of Biological Chemistry

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“…In vivo, rapamycin treatment reduced the tumor burden and increased survival in TSC-deficient animal models developing renal tumors (Kenerson et al, 2005;Lee et al, 2005Lee et al, , 2006Pollizzi et al, 2009;Woodrum et al, 2010).…”

Section: The Mtorc1 Inhibitors As Treatment For Tscmentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…41,42 Given the considerable experience with rapamycin in human populations, translation of the pre-clinical findings to human clinical trials was rapid. Bissler et al 43 reported a singlesite, phase I/II open-label study of rapamycin for the treatment of renal AML in 25 patients with TSC or sporadic LAM.…”

Section: Treatment Of the Physical Features Of Tscmentioning

confidence: 99%

Targeted Treatments for Cognitive and Neurodevelopmental Disorders in Tuberous Sclerosis Complex

Vries

2010

Neurotherapeutics

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Summary:Until recently, the neuropsychiatric phenotype of tuberous sclerosis complex (TSC) was presumed to be caused by the structural brain abnormalities and/or seizures seen in the disorder. However, advances in the molecular biology of the disorder have shown that TSC is a mammalian target of rapamycin (mTOR) overactivation syndrome, and that direct molecular pathways exist between gene mutation and cognitive/ neurodevelopmental phenotype. Molecularly-targeted treatments using mTOR inhibitors (such as rapamycin) are showing great promise for the physical and neurological phenotype of TSC. Pre-clinical and early-phase clinical studies of the cognitive and neurodevelopmental features of TSC suggest that some of the neuropsychiatric phenotypes might also be reversible, even in adults with the disorder. TSC, fragile X, neurofibromatosis type 1, and disorders associated with phosphatase and tensin homo (PTEN) mutations, all signal through the mTOR signaling pathway, with the TSC1-TSC2 protein complex as a molecular switchboard at its center. Together, these disorders represent as much as 14% of autism spectrum disorders (ASD). Therefore, we suggest that this signaling pathway is a key to the underlying pathophysiology of a significant subset of individuals with ASD. The study of molecularly targeted treatments in TSC and related disorders, therefore, may be of scientific and clinical value not only to those with TSC, but to a larger population that may have a neuropsychiatric phenotype attributable to mTOR overactivation or dysregulation.

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Efficacy of a rapamycin analog (CCI‐779) and IFN‐γ in tuberous sclerosis mouse models

Cited by 159 publications

References 38 publications

Inactivation of Mammalian Target of Rapamycin Increases STAT1 Nuclear Content and Transcriptional Activity in α4- and Protein Phosphatase 2A-dependent Fashion

Inactivation of Mammalian Target of Rapamycin Increases STAT1 Nuclear Content and Transcriptional Activity in α4- and Protein Phosphatase 2A-dependent Fashion

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Targeted Treatments for Cognitive and Neurodevelopmental Disorders in Tuberous Sclerosis Complex

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