Journal ArticleDOI
Cell-cycle checkpoints and cancer
Michael B. Kastan,Jiri Bartek +1 more
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TLDR
All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation, and how cells respond to DNA damage are critical determinants of whether that individual will develop cancer.Abstract:
All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation. Highly conserved DNA-repair and cell-cycle checkpoint pathways allow cells to deal with both endogenous and exogenous sources of DNA damage. How much an individual is exposed to these agents and how their cells respond to DNA damage are critical determinants of whether that individual will develop cancer. These cellular responses are also important for determining toxicities and responses to current cancer therapies, most of which target the DNA.read more
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Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine
Ruben A. Mesa,David A. Loegering,Heather Powell,Karen S. Flatten,Sonnet J.H. Arlander,Nga T. Dai,Michael P. Heldebrant,Benjamin T. Vroman,B. Douglas Smith,Judith E. Karp,Cynthia Ten Eyck,Charles Erlichman,Scott H. Kaufmann,Larry M. Karnitz +13 more
TL;DR: Treatment with 17-AAG might represent a means of reversing checkpoint-mediated cytarabine resistance in AML, according to results of this study.
Journal ArticleDOI
ATR and Chk1 suppress a caspase-3-dependent apoptotic response following DNA replication stress
TL;DR: It is shown that depletion of ATM or its downstream phosphorylation targets, NBS1 and BID, has relatively little effect on apoptosis induced by DNA replication inhibitors, while ATR or Chk1 depletion strongly enhances cell death induced by such agents in all cells tested.
Journal ArticleDOI
Poly(ADP-Ribose) Polymerase Inhibition as a Model for Synthetic Lethality in Developing Radiation Oncology Targets
TL;DR: Because biologically active doses of PARP inhibitors caused minimal toxicity in phase I to II clinical trials, careful scheduling of these agents in combination with radiotherapy may maintain the therapeutic ratio and increase tumor radiocurability.
Journal ArticleDOI
The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer.
Johanna Tommiska,J Bartkova,Mira Heinonen,Laura Hautala,Outi Kilpivaara,Hannaleena Eerola,Kristiina Aittomäki,Barbara Hofstetter,Jiri Lukas,K. von Smitten,Carl Blomqvist,Ari Ristimäki,Päivi Heikkilä,J Bartek,Heli Nevanlinna +14 more
TL;DR: A model of ‘conditional haploinsufficiency’ for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM is proposed, with implications for genomic instability and curability of diverse subsets of human breast cancer.
Journal ArticleDOI
Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study
Anne Hansen Ree,Anne Hansen Ree,Svein Dueland,Sigurd Folkvord,Knut Håkon Hole,Therese Seierstad,Therese Seierstad,Marianne Johansen,Torveig Weum Abrahamsen,Kjersti Flatmark +9 more
TL;DR: This study highlights the potential use of HDAC inhibitors with radiation, and suggests investigation of vorinostat in long-term curative pelvic radiotherapy--eg, as a component of preoperative chemoradiotherapy for rectal cancer.
References
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Book
The Causes of Cancer: Quantitative Estimates of Avoidable Risks of Cancer in the United States Today
Richard Doll,Richard Peto +1 more
TL;DR: Evidence that the various common types of cancer are largely avoidable diseases is reviewed, and it is suggested that, apart from cancer of the respiratory tract, the types of cancers that are currently common are not peculiarly modern diseases and are likely to depend chiefly on some long-established factor.
Journal ArticleDOI
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
TL;DR: It is shown that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described ‘FAT’ domain.
Journal ArticleDOI
Checkpoints: controls that ensure the order of cell cycle events
Leland H. Hartwell,Ted Weinert +1 more
TL;DR: It appears that some checkpoints are eliminated during the early embryonic development of some organisms; this fact may pose special problems for the fidelity of embryonic cell division.
Journal ArticleDOI
Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes
Lee Zou,Stephen J. Elledge +1 more
TL;DR: The data suggest that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling.
Journal ArticleDOI
ATM and related protein kinases: safeguarding genome integrity
TL;DR: Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.