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
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Journal ArticleDOI
Perturbations of the AKT signaling pathway in human cancer
TL;DR: Various pathogenic mechanisms contributing to activation of the AKT pathway in human malignancy as well as current pharmacologic strategies to target therapeutically components of this pathway are reviewed.
Journal ArticleDOI
Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis.
TL;DR: The tumour-suppressor phosphatase with tensin homology (PTEN) is the most important negative regulator of the cell-survival signalling pathway initiated by phosphatidylinositol 3-kinase (PI3K), and deregulation of the PI3K–PTEN network occurs through other mechanisms.
Journal ArticleDOI
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer
John D. Carpten,Andrew L. Faber,Candice Horn,Gregory P. Donoho,Stephen L. Briggs,Christiane M. Robbins,Galen Hostetter,Sophie Boguslawski,Tracy Moses,Stephanie Savage,Mark Uhlik,Aimin Lin,Jian Du,Yue-Wei Qian,Douglas J. Zeckner,Greg Tucker-Kellogg,Jeffrey W. Touchman,Ketan J. Patel,Spyro Mousses,Michael L. Bittner,Richard W. Schevitz,Mei-Huei T. Lai,Kerry L. Blanchard,James E. Thomas +23 more
TL;DR: The identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1 is reported.
Journal ArticleDOI
G1 cell-cycle control and cancer
TL;DR: An increasingly complex and coherent view of G1 signalling networks, which coordinate cell growth, proliferation, stress management and survival, is helping to define the roots of malignancies and shows promise for the development of better cancer therapies.
Journal ArticleDOI
Transcriptional regulation and transformation by Myc proteins
Sovana Adhikary,Martin Eilers +1 more
TL;DR: A wealth of data has shed new light on the biochemical functions of Myc proteins and on the mechanisms through which they function in cellular transformation.
References
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Journal ArticleDOI
The hallmarks of cancer.
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
TL;DR: Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.
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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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