Mol Cancer Res author manuscript in PMC 2009 1 July. Phosphorylation of ATM by Cdk5 signaling mediator of DNA-Sch Regulates the neuronal death and Bo Tian1, 2, Qian Yang1, Limonin 2 and Zixu MAO1, 2.3 1Departments of Pharmacology and Neurology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30 322, USA 2Center for Neurodegenerative Diseases, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30 322, USA Abstract The ATM kinase phosphatidylinositol 3-kinase plays a like in coordinating the response to DNA-Sch the ‘confinement controlled Lich of the control point of the cell cycle, DNA repair and apoptosis. ATM mutations cause a spectrum of defects in the range of neurodegeneration, cancer Pr Disposition. However, the mechanism of DNA is Sch Ending ATM activates poorly understood.
We show that Cdk5, activated by DNA-Sch Ending, ATM directly phosphorylates serine 794 in post-mitotic neurons. The phosphorylation of serine 794 and above is for ATM autophosphorylation at serine 1981 is required and activated ATM kinase activity t. Cdk5-ATM signal Masitinib regulates phosphorylation and function of the ATM targets p53 and H2AX. Interruption of the Cdk5 ATM path D Mpft DNA Sch By the return of the neuronal cell cycle and expression of p53 and Bax induced PUMA objectives, protection of neurons from DNA Sch The-induced death. Thus serves to activate Cdk5 by DNA Sch Ending as a critical signal for the reaction of ATM and ATM-regulation of cellular To initiate Ren processes.
DNA Sch Transduced ending signals to activate a key family of phosphoinositide 3-kinase-related kinases, such as ATM, which a number of proteins important for controlled L checkpoints phosphorylated The cellular cycle Ren DNA repair and in case of Besch Ending above the cell’s DNA Owned death.1, 2, 3 As ATM activity is t by the signal DNA-Sch The regulated, is unclear. Earlier studies have shown that activation of ATM autophosphorylation comprises of several serine residues, including normal S19814, 5 The widely accepted model is that autophosphorylation of ATM at S1981 she l St inhibitory homodimer structure, leading to their activation and recruitment to sites of DNA double-strand break 6, but a recently published Ffentlichter report questions the R The S1987, S1981 corresponds to the mouse, in the DNA damage-induced activation of ATM in vivo7.
Unlike the proliferation of cells in which DNA-Sch The generally L St control points The cell cycle, activate postmitotic neurons under conditions of genotoxic stress including normal stimulation of their cell cycle machinery8. This cell cycle reentry leads to neuronal death of postmitotic neurons and inhibiting the activity of t such ectopic cell cycle protects neurons9-12. Studies of emission ATM-/-mice that ATM for p53-mediated apoptosis of postmitotic neurons exposed radiation13 ionizing development, 14 is not required. The suppression of ATM d Mpft 3Correspondence DNA-Sch Should be addressed to the ZM. ZM AUTHOR CONTRIBUTION coordinated to plan the entire project and the original experimental design. T. B. and Q. Y. Experiments were performed. ZM and BT analyzed data and wrote the paper.
Competing financial interests The authors explained Ren, they have no competing financial interests. NIH manuscript authors access Public at Nat Cell Biol author manuscript in PMC 12th October 2009. Ver published in its final form: Nat Cell Biol, 2009, 11: 211 18 �. doi: 10.1038/ncb1829. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript agent camptothecin-induced cell cycle reentry by postmitotic neurons15 and death. These results establish the r The ATM in DNA-Sch The-induced neuronal death. Cdk5, has a small serine / threonine kinase is an activator p35, but not cell cycle regulated, has been shown to play an R In the neuronal stress response16, 17, 18 Examination of the protein sequence o