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Yosef Shiloh

Bio: Yosef Shiloh is an academic researcher from Tel Aviv University. The author has contributed to research in topics: Ataxia-telangiectasia & DNA damage. The author has an hindex of 75, co-authored 200 publications receiving 34100 citations. Previous affiliations of Yosef Shiloh include German Cancer Research Center & Weizmann Institute of Science.


Papers
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Journal ArticleDOI
25 May 2007-Science
TL;DR: A large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR is performed and more than 900 regulated phosphorylation sites encompassing over 700 proteins are identified.
Abstract: Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). The outlines of the signal transduction portion of this pathway are known, but little is known about the physiological scope of the DNA damage response (DDR). We performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this data set indicated that this list is highly enriched for proteins involved in the DDR. This set of proteins is highly interconnected, and we identified a large number of protein modules and networks not previously linked to the DDR. This database paints a much broader landscape for the DDR than was previously appreciated and opens new avenues of investigation into the responses to DNA damage in mammals.

2,967 citations

Journal ArticleDOI
23 Jun 1995-Science
TL;DR: A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia was identified by positional cloning on chromosome 11q22-23 and encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control.
Abstract: A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer.

2,729 citations

Journal ArticleDOI
Yosef Shiloh1
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.
Abstract: Maintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response--a cornerstone of genome stability--occurs by a swift transduction of the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA double-strand breaks, which activate the ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). 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.

2,579 citations

PatentDOI
26 Aug 1999-Science
TL;DR: A diagnostic tool for determining the presence of A-T having a detector for detecting ATMprotein levels and quantification tools for analyzing the ATM protein levels is also provided in this paper.
Abstract: There are provided antibodies directed against the ATM protein are peptide derivatives of the protein are also provided. Also provided is a diagnostic tool for determining the presence of A-T having a detector for detecting ATM protein levels and quantification tools for analyzing the ATM protein levels. A kit for detecting the presence of A-T containing a detector for detecting ATM protein levels and a quantificator for analyzing ATM protein levels is also provided.

1,869 citations

Journal ArticleDOI
12 Jul 1996-Cell
TL;DR: Atm-disrupted mice recapitulate the ataxia telangiectasia phenotype in humans, providing a mammalian model in which to study the pathophysiology of this pleiotropic disorder.

1,467 citations


Cited by
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Journal ArticleDOI
TL;DR: The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases.
Abstract: ▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that...

5,833 citations

Journal ArticleDOI
TL;DR: In this paper, a histone H2AX species that has been phosphorylated specifically at serine 139 was found to be a major component of DNA double-stranded break.

5,132 citations

Journal ArticleDOI
22 Oct 2009-Nature
TL;DR: The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases.
Abstract: The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.

4,871 citations

Journal ArticleDOI
TL;DR: The purposes of this review are to highlight examples of progress in many areas of cancer research, indicate where knowledge is scarce and point out fertile grounds for future investigation.
Abstract: The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.

4,159 citations

Journal ArticleDOI
17 Dec 1998-Nature
TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
Abstract: Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.

4,121 citations