| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Molecular Biology, University of Texas Health Center at Tyler, Tyler, Texas 75703
Submitted 25 June 2002 ; accepted in final form 29 August 2003
Hyperoxia has been shown to cause DNA damage resulting in growth arrest of cells in p53-dependent, as well as p53-independent, pathways. Although H2O2 and other peroxides have been shown to induce ataxia telangiectasia-mutated (ATM)-dependent p53 phosphorylation in response to DNA damage, the signal transduction mechanisms in response to hyperoxia are currently unknown. Here we demonstrate that hyperoxia phosphorylates the Ser15 residue of p53 independently of ATM. Hyperoxia phosphorylated p53 (Ser15) in DNA-dependent protein kinase null (DNA-PK-/-) cells, indicating that it may not depend on DNA-PK for phosphorylation of p53 (Ser15). We show that Ser37 and Ser392 residues of p53 are also phosphorylated in an ATM-independent manner in hyperoxia. In contrast, H2O2 did not phosphorylate Ser37 in either ATM+/+ or ATM-/- cells. Furthermore, H2O2 failed to phosphorylate Ser15 in ATM-/- cells. Additionally, overexpression of kinase-inactive ATM-and-Rad3-related (ATR) in HEK293T cells diminished Ser15, Ser37, and Ser392 phosphorylation compared with vector-only transfected cells. In contrast, wild-type ATR overexpression did not diminish Ser15, Ser37, or Ser392 phosphorylation. We also show that checkpoint kinase 1 (Chk1) is phosphorylated on Ser345 in response to hyperoxia, which could be inhibited by caffeine or wortmannin, potent inhibitors of phosphoinositide 3-kinase-related kinases. Hyperoxia also phosphorylated Chk1 in ATM+/+ as well as in ATM-/- cells, demonstrating an ATM-independent mechanism in Chk1 phosphorylation. Together, our data suggest that hyperoxia activates the ATR-Chk1 pathway and phosphorylates p53 at multiple sites in an ATM-independent manner, which is different from other forms of oxidative stress such as H2O2 or UV light.
serine-15; ataxia telangiectasia mutated; ATM and Rad3 related; phosphoinositide 3-kinase-related kinase; DNA-dependent protein kinase; checkpoint kinase 1; hydrogen peroxide; ultraviolet; serine-392; serine-37
This article has been cited by other articles:
|
|
 |
|
  A. Kulkarni and K. C. Das Differential roles of ATR and ATM in p53, Chk1, and histone H2AX phosphorylation in response to hyperoxia: ATR-dependent ATM activation Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L998 - L1006. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Mroz, R. P. F. Schins, H. Li, L. A. Jimenez, E. M. Drost, A. Holownia, W. MacNee, and K. Donaldson Nanoparticle-driven DNA damage mimics irradiation-related carcinogenesis pathways Eur. Respir. J., February 1, 2008; 31(2): 241 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-L. Chen, F. Pistollato, D. J. Hoeppner, H.-T. Ni, R. D.G. McKay, and D. M. Panchision Oxygen Tension Regulates Survival and Fate of Mouse Central Nervous System Precursors at Multiple Levels Stem Cells, September 1, 2007; 25(9): 2291 - 2301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. O'Brien, V. Barnes, L. Zhao, R. A. McKnight, X. Yu, C. W. Callaway, L. Wang, J. C. Sun, M. J. Dahl, A. Wint, et al. Uteroplacental insufficiency decreases p53 serine-15 phosphorylation in term IUGR rat lungs Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R314 - R322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. LaRocque, D. L. Dougherty, S. K. Hussain, and J. Sekelsky Reducing DNA Polymerase {alpha} in the Absence of Drosophila ATR Leads to P53-Dependent Apoptosis and Developmental Defects Genetics, July 1, 2007; 176(3): 1441 - 1451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. LaRocque, B. Jaklevic, T. T. Su, and J. Sekelsky Drosophila ATR in Double-Strand Break Repair Genetics, March 1, 2007; 175(3): 1023 - 1033. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
