MICHAEL BARRY KASTAN

..Although it is hard to understand how a single gene product is involved in so many physiological processes, a clear picture is starting to emerge...

..These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease...

..Conversely, activators of ATM could improve responses to cellular stresses such as oxidative damage. The potential benefits of ATM modulation in disease settings ranging from metabolic syndrome to cancer will be discussed...

..These cellular responses are also important for determining toxicities and responses to current cancer therapies, most of which target the DNA...

..Relevant to the latter, we have shown benefits of an ATM activator in disease settings ranging from metabolic syndrome to cancer prevention...

..Martins et al. (2006) also demonstrate that restoration of p53 activity results in tumor regression but add the sobering caveat that tumors may be able to quickly generate resistance by finding other ways to disrupt the p53 pathway...

..Such insights also result in the identification of potential new targets for enhancing the efficacy of radiation therapy...

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..Therefore, regulation of cell proliferation and p27(Kip1) seems to be a contributing mechanism by which Atm holds tumor formation in check...

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..These results demonstrate that Smc1 participates in cellular responses to DNA damage and link Smc1 to the Atm signal transduction pathway...

..The ability of CP466722 to rapidly and reversibly regulate ATM activity provides a new tool to ask questions about ATM function that could not easily be addressed using genetic models or RNA interference technologies...

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..These observations suggest that many of the abnormal stress responses seen in cells lacking ATM, NBS1, or BRCA1 result from a failure of ATM migration to sites of DNA breaks and a resultant lack of SMC1 phosphorylation...

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..1) that rearranged BCL6 and placed it adjacent to MYC. We speculate that this genetic lesion occurred as a result of chromosomal instability due to the underlying disease...

..Host immunity and appropriate DNA damage responses are critical inhibitors of carcinogenesis. Therefore, we sought to determine the long-term effects of ALL treatment on immune function and response to DNA damage...

..This demonstrates that loss of this checkpoint function by itself does not affect cell survival and suggests that some other function of Brca1 alters cell survival after DNA damage...

..Thus, two different G(2) arrest mechanisms are present in mammalian cells, and the type of cell cycle checkpoint assay to be used in experimental investigation must be thoughtfully selected...

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..These findings demonstrate the importance of increased translation of p53 in DNA-damage responses and suggest critical roles for RPL26 and nucleolin in affecting p53 induction...

..Control mechanisms include the localization of PIKKs into multiprotein complexes at the sites of damage and mediation of protein-protein contacts such that substrates are allowed access to the PIKK catalytic domains...

..Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis...

..Three recent articles describe roles for two phosphatases in signaling pathways that are activated after DNA damage...

..The ability to reduce stress induction of p53 with oligonucleotides or other small molecules has numerous potential therapeutic uses...

..Thus, niacinamide and thiamine form a novel basis for the development of small molecules that affect p53 function in vivo, and these results suggest that changes in cellular energy metabolism may regulate p53...

..Attempts to replicate in the presence of these lesions would result in gradual accumulation of mutations, leading to genome instability and cellular transformation...

..Our results indicate that a short prior exposure to chloroquine may have a preventative application for mammary carcinogenesis...

..Collectively, the results of these studies demonstrate a novel pathway that links ATM, PP1, and I-2 in the cellular response to DNA damage...

..These results suggest that low-dose UV radiation activates an S-phase checkpoint requiring ATR-mediated signal transduction pathway...

..Together, these data demonstrate that multiple functional domains of NBS1 are required for ATM-dependent activation of CHK2, nuclear focus formation, S phase checkpoint control, and cell survival after exposure to IR...

..NBS1 and FANCD2 therefore cooperate in two distinct cellular functions, one involved in the DNA crosslink response and one involved in the S-phase checkpoint response...

..Biallelic disruption of FANCD2 results in both MMC and IR hypersensitivity...

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..The new tools characterized here should facilitate monitoring of ATM activation in clinical specimens, and help develop future treatment strategies...

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..We propose that subclassification of DSB regulators according to their residence sites provides a useful framework for understanding their involvement in diverse processes of genome surveillance...

..Although not absolutely required for ATM activation, the MRN nuclease complex may help reach the threshold activity of ATM necessary for optimal genome maintenance and prevention of cancer...

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..Furthermore, they suggest that mutations in BRCA1 or interacting proteins could lead to rearrangements at fragile sites in cancer cells...

..Starting with fragmented chromatin, results can be achieved in 2-3 d...

..These studies will help us understand how cells respond to DNA damage and other stresses at the molecular level. ..

..This manpower concern is particularly acute in Pediatric subspecialties. Graduates of the training program supported by this application will fill this critical need. ..

..In tow, these studies should provide significant new information that has implications for both tumor development and therapy. ..

..St. Jude Children's Research Hospital recently went through a vigorous Strategic Planning process and made a strong and long-term commitment to remain focused on cancer research. ..

..Experiments are proposed to further explore the molecular mechanisms involved in both the radioprotective effects and the cancer preventative effects of ATM activation. ..

..Significant insights into the role of SMC1 phosphorylation can be gained by studies of the organ development and responses to irradiation as well as from generation of cell lines from these mice. ..

..These studies also have therapeutic implications since inhibition of ATM function should cause increased tumor cell death in response to a number of anti-neoplastic therapies. ..

..4) A neuroblastoma model system in which irradiation-induced differentiation is dependent on p53 will be used to clarify the roles of Gadd45, N-myc, Mad-3 and cdc25 in this process. ..

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..These studies will help us understand how cells respond to DNA damage and other stresses at the molecular level. ..