HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Buy All Versions of this Article: fj.08-114256v1 23/3/783    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Klimova, T. A. Articles by Chandel, N. S. Search for Related Content PubMed PubMed Citation Articles by Klimova, T. A. Articles by Chandel, N. S.

Hyperoxia-induced premature senescence requires p53 and pRb, but not mitochondrial matrix ROS

Tatyana A. Klimova^*, Eric L. Bell^*, Emelyn H. Shroff^*, Frank D. Weinberg^*, Colleen M. Snyder^*, Goberdan P. Dimri^,, Paul T. Schumacker, G. R. Scott Budinger^* and Navdeep S. Chandel^*,,1

^* Department of Medicine and

Department of Pediatrics, Northwestern University, Chicago, Illinois;

Division of Cancer Biology and Department of Medicine, Evanston Northwestern Hospital Research Institute, and

Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Evanston, Illinois, USA

¹Correspondence: McGaw Pavilion, 240 East Huron Ave., Rm. M-334, Chicago, IL 60611, USA. E-mail: nav{at}northwestern.edu

Senescence is a potential tumor-suppressing mechanism and a commonly used model of cellular aging. One current hypothesis to explain senescence, based in part on the correlation of oxygen with senescence, postulates that it is caused by oxidative damage from reactive oxygen species (ROS). Here, we further test this theory by determining the mechanisms of hyperoxia-induced senescence. Exposure to 70% O₂ led to stress-induced, telomere-independent senescence. Although hyperoxia elevated mitochondrial ROS production, overexpression of antioxidant proteins was not sufficient to prevent hyperoxia-induced senescence. Hyperoxia activated AMPK; however, overexpression of a kinase-dead mutant of LKB1, which prevented AMPK activation, did not prevent hyperoxia-induced senescence. Knocking down p21 via shRNA, or suppression of the p16/pRb pathway by either BMI1 or HPV16-E7 overexpression, was also insufficient to prevent hyperoxia-induced senescence. However, suppressing p53 function resulted in partial rescue from senescence, suggesting that hyperoxia-induced senescence involves p53. Suppressing both the p53 and pRb pathways resulted in almost complete protection, indicating that both pathways cooperate in hyperoxia-induced senescence. Collectively, these results indicate a ROS-independent but p53/pRb-dependent senescence mechanism during hyperoxia.—Klimova, T. A., Bell, E. L., Shroff, E. H., Weinberg, F. D., Snyder, C. M., Dimri, G. P., Schumacker, P. T., Budinger, G. R. S., Chandel, N. S. Hyperoxia-induced premature senescence requires p53 and pRb, but not mitochondrial matrix ROS.

Key Words: AMPK • cell cycle • telomerase

This article has been cited by other articles:

				G. A. Gusarova, L. A. Dada, A. M. Kelly, C. Brodie, L. A. Witters, N. S. Chandel, and J. I. Sznajder {alpha}1-AMP-Activated Protein Kinase Regulates Hypoxia-Induced Na,K-ATPase Endocytosis via Direct Phosphorylation of Protein Kinase C{zeta} Mol. Cell. Biol., July 1, 2009; 29(13): 3455 - 3464. [Abstract] [Full Text] [PDF]