Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation

Baskaran, Rathinasamy; Wood, Lauren D.; Whitaker, Laura; Canman, Christine E.; Morgan, Susan E.; Xu, Yiming; Barlow, Carrolee; Baltimore, David; Wynshaw‐Boris, Anthony; Kastan, Michael B.; Wang, J. Y J

doi:10.1038/387516a0

Cited by 500 publications

(400 citation statements)

References 22 publications

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“…ATM is required for the e cient activation of c-Abl by IR (Shafman et al, 1997;Baskaran et al, 1997). The SH3 domain of c-Abl interacts with a proline-rich motif in ATM (Shafman et al, 1997), and the ATMkinase domain was shown in vitro to phosphorylate cAbl on Ser-465 (Baskaran et al, 1997).…”

Section: Responses Mediated By Jnk and C-ablmentioning

confidence: 99%

ATM: A mediator of multiple responses to genotoxic stress

1999

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The ATM protein kinase is the product of the gene responsible for the pleiotropic recessive disorder ataxiatelangiectasia. ATM-de®cient cells show enhanced sensitivity and greatly reduced responses to genotoxic agents that generate DNA double strand breaks (DSBs), such as ionizing radiation and radiomimetic chemicals, but exhibit normal responses to DNA adducts and base modi®cations induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identi®cation of the ATM gene triggered extensive research aimed at elucidating the numerous functions of its large multifaceted protein product. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in the nucleus where it plays a central role in the very early stages of damage detection and serves as a master controller of cellular responses to DSBs. By activating key regulators of multiple signal transduction pathways, ATM mediates the e cient induction of a signaling network responsible for repair of the damage, and for cellular recovery and survival.

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Section: Responses Mediated By Jnk and C-ablmentioning

confidence: 99%

ATM: A mediator of multiple responses to genotoxic stress

1999

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“…The ®nding that c-Abl is present near the ends of certain pachytene chromosomes raises the possibility that c-Abl is involved in telomere movement. In this context, recent studies have demonstrated that c-Abl interacts with ATM (Baskaran et al, 1997;Shafman et al, 1997). ATM, a homolog of the yeast TEL1 (Greenwell et al, 1995), has been found to in¯uence telomeric associations and control telomere length in mammalian cells (Smilenov et al, 1997).…”

Section: (And Data Not Shown)mentioning

confidence: 99%

“…Activation of DNA ± PK by DNA damage results in phosphorylation of c-Abl and induction of c-Abl activity . Other studies have demonstrated that c-Abl associates with the ataxia telangiectasia mutated (ATM) gene product and that ATM may activate c-Abl in the response to DNAdamaging agents (Baskaran et al, 1997;Shafman et al, 1997). Cells de®cient in c-Abl are resistant to DNAdamage-induced apoptosis , while DNA ± PK or ATM-de®cient cells are hypersensitive to radiation (Jeggo et al, 1995;Roth et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Functional role for the c-Abl tyrosine kinase in meiosis I

et al. 1998

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The c-Abl tyrosine kinase is activated by ionizing radiation and certain other DNA-damaging agents. The DNA-dependent protein kinase (DNA ± PK) and the ataxia telangiectasia mutated (ATM) gene product, e ectors in the DNA damage response, contribute to the induction of c-Abl activity. The present study demonstrates that c-Abl is expressed in mouse and rat testes, and predominantly in pachytene spermatocytes of meiosis I. The results also demonstrate that c-Abl interacts directly with meiotic chromosomes. In concert with a requirement for c-Abl at the pachytene stage, we show that, in contrast to wild-type mice, testes from Abl 7/7 mice exhibit defects in spermatogenesis. These ®ndings provide the ®rst demonstration that c-Abl plays a functional role in meiosis.

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“…We have previously shown that overexpression of p53 in A-T cells is capable of activating the G1/S checkpoint but was unable to change the radiosensitive status of these cells . Defective interaction between ATM and the protein tyrosine kinase c-Abl, and as a consequence a failure to observe c-Abl kinase activation post-irradiation, could also contribute to the G1/S checkpoint abnormality (Baskaran et al, 1997;Khanna et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells

et al. 1999

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Cells from patients with the human genetic disorder ataxia-telangiectasia (A-T) are defective in the activation of cell cycle checkpoints in response to ionizing radiation damage. In order to understand the role of ATM in checkpoint control we investigated whether Schizosaccaromyces pombe chk1, a protein kinase implicated in controlling the G2 DNA damage checkpoint, might alter the radiosensitive phenotype in A-T cells. The ®ssion yeast chk1 gene was cloned into an EBV-based vector under the control of a metallothionein promoter and transfected into A-T lymphoblastoid cells. Induction of chk1 enhanced the survival of an A-T cell line in response to radiation exposure as determined by cell viability and reduction of radiation-induced chromosome aberrations. This can be accounted for at least in part by the restoration of the G2 checkpoint to chk1 expressing cells. There was no evidence that chk1 expression corrected either the G1/S checkpoint or radioresistant DNA synthesis in S phase in these cells. These results suggest that chk1 when overexpressed acts downstream from ATM to restore the G2 checkpoint in these cells and correct the radiosensitive phenotype. These data allow us to dissociate individual checkpoint events and relate them to the radiosensitive phenotype in A-T cells.

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Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation

Cited by 500 publications

References 22 publications

ATM: A mediator of multiple responses to genotoxic stress

ATM: A mediator of multiple responses to genotoxic stress

Functional role for the c-Abl tyrosine kinase in meiosis I

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells

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