Cell Cycle Activation Linked to Neuronal Cell Death Initiated by DNA Damage

Increasing evidence indicates that neurodegeneration involves the activation of the cell cycle machinery in postmitotic neurons. However, the purpose of these cell cycle-associated events in neuronal apoptosis remains unknown. Here we tested the hypothesis that cell cycle activation is a critical co...

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Veröffentlicht in:Neuron (Cambridge, Mass.) Mass.), 2004-02, Vol.41 (4), p.549-561
Hauptverfasser: Kruman, Inna I, Wersto, Robert P, Cardozo-Pelaez, Fernando, Smilenov, Lubomir, Chan, Sic L, Chrest, Francis J, Emokpae, Roland, Gorospe, Myriam, Mattson, Mark P
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container_end_page 561
container_issue 4
container_start_page 549
container_title Neuron (Cambridge, Mass.)
container_volume 41
creator Kruman, Inna I
Wersto, Robert P
Cardozo-Pelaez, Fernando
Smilenov, Lubomir
Chan, Sic L
Chrest, Francis J
Emokpae, Roland
Gorospe, Myriam
Mattson, Mark P
description Increasing evidence indicates that neurodegeneration involves the activation of the cell cycle machinery in postmitotic neurons. However, the purpose of these cell cycle-associated events in neuronal apoptosis remains unknown. Here we tested the hypothesis that cell cycle activation is a critical component of the DNA damage response in postmitotic neurons. Different genotoxic compounds (etoposide, methotrexate, and homocysteine) induced apoptosis accompanied by cell cycle reentry of terminally differentiated cortical neurons. In contrast, apoptosis initiated by stimuli that do not target DNA (staurosporine and colchicine) did not initiate cell cycle activation. Suppression of the function of ataxia telangiectasia mutated (ATM), a proximal component of DNA damage-induced cell cycle checkpoint pathways, attenuated both apoptosis and cell cycle reentry triggered by DNA damage but did not change the fate of neurons exposed to staurosporine and colchicine. Our data suggest that cell cycle activation is a critical element of the DNA damage response of postmitotic neurons leading to apoptosis.
doi_str_mv 10.1016/S0896-6273(04)00017-0
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subjects Animals
Apoptosis
Apoptosis - drug effects
Apoptosis - genetics
Ataxia Telangiectasia Mutated Proteins
Cell cycle
Cell Cycle - drug effects
Cell Cycle - genetics
Cell Cycle Proteins
Cell death
Cells, Cultured
Colchicine - pharmacology
DNA damage
DNA Damage - drug effects
DNA Damage - genetics
DNA repair
DNA-Binding Proteins
Etoposide - pharmacology
Female
Homocysteine - pharmacology
Kinases
Male
Methotrexate - pharmacology
Mice
Nerve Degeneration - genetics
Nerve Degeneration - metabolism
Neurons - drug effects
Neurons - metabolism
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - genetics
Rats
Staurosporine - pharmacology
Tumor Suppressor Proteins
title Cell Cycle Activation Linked to Neuronal Cell Death Initiated by DNA Damage
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