The gene that encodes the ATM protein kinase is mutated in ataxia-telangiectasia 
(A-T). One of the prominent features of A-T is progressive neurodegeneration. We 
have previously reported that primary astrocytes isolated from Atm(-/-) mice 
grow slowly and die earlier than control cells in culture. However, the 
mechanisms for this remain unclear. We show here that intrinsic elevated 
intracellular levels of reactive oxygen species (ROS) are associated with the 
senescence-like growth defect of Atm(-/-) astrocytes. This condition is 
accompanied by constitutively higher levels of ERK1/2 phosphorylation and 
p16(Ink4a) in Atm(-/-) astrocytes. We also observe that ROS-induced 
up-regulation of p16(Ink4a) occurs correlatively with ERK1/2-dependent 
down-regulation and subsequent dissociation from chromatin of Bmi-1. 
Furthermore, both mitogen-activated protein kinase (MAPK)/ERK inhibitor PD98059 
and antioxidant N-acetyl-l-cysteine restored normal proliferation of Atm(-/-) 
astrocytes. These results suggest that ATM is required for normal astrocyte 
growth through its ability to stabilize intracellular redox status and that the 
inability to control ROS is the molecular basis of limited cell growth of 
Atm(-/-) astrocytes. This defect may be mediated by a mechanism involving ERK1/2 
activation and Bmi-1 derepression of p16(Ink4a). These data identify new 
potential targets for therapeutic intervention in A-T neurodegeneration.