Journal ArticleDOI
Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy.
Hans-Guido Wendel,Elisa de Stanchina,Jordan S. Fridman,Jordan S. Fridman,Abba Malina,Sagarika Ray,Scott C. Kogan,Carlos Cordon-Cardo,Jerry Pelletier,Scott W. Lowe +9 more
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TLDR
It is shown that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects.Abstract:
Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.read more
Citations
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Journal ArticleDOI
Regulation of mTOR and Cell Growth in Response to Energy Stress by REDD1
TL;DR: RedD1 is demonstrated to be a critical transducer of the cellular response to energy depletion through the TSC-mTOR pathway.
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Targeting mammalian target of rapamycin (mTOR) for health and diseases.
TL;DR: These findings demonstrate the importance of growth control in the pathology of major diseases and overall human health, and underscore the therapeutic potential of the mTOR pathway.
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The survival kinases Akt and Pim as potential pharmacological targets.
TL;DR: The Akt and Pim kinases are cytoplasmic serine/threonine kinases that control programmed cell death by phosphorylating substrates that regulate both apoptosis and cellular metabolism.
Journal ArticleDOI
Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?
TL;DR: This review highlights recent advances in the mTOR signaling field that relate to how the two mTOR complexes are regulated, and discusses stress conditions linked to the m TOR signaling network that have not been extensively covered in other reviews.
Journal ArticleDOI
Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways
TL;DR: In the absence of either TSC1 or TSC2, high levels of Rheb-GTP lead to constitutive activation of mTOR-raptor signaling, thereby leading to enhanced and deregulated protein synthesis and cell growth.
References
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TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
Journal ArticleDOI
The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
Igor Vivanco,Charles L. Sawyers +1 more
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Cellular survival: a play in three Akts
TL;DR: The mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI 3K/ c-AKT pathway promotes cell survival, and the current spectrum of c- akt targets and their roles in mediating c- Akt-dependent cell survival are reviewed.
Journal ArticleDOI
Identification of a candidate tumour suppressor gene, MMAC1 , at chromosome 10q23.3 that is mutated in multiple advanced cancers
Peter A. Steck,Mark A. Pershouse,Samar A. Jasser,W. K. A. Yung,Huai Lin,Azra H. Ligon,Lauren A. Langford,Michelle Baumgard,T. Hattier,Thaylon Davis,Cheryl Frye,Rong Hu,Bradley D. Swedlund,David H. F. Teng,Sean V. Tavtigian +14 more
TL;DR: The results identify a strong candidate tumour suppressor gene at chromosome 10q23.3, whose loss of function appears to be associated with the oncogenesis of multiple human cancers.
Journal ArticleDOI
NF-κB in cancer: from innocent bystander to major culprit
TL;DR: Recent evidence indicates that NF-κB and the signalling pathways that are involved in its activation are also important for tumour development.
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