This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Limesand, K. H.
Right arrow Articles by Anderson, S. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Limesand, K. H.
Right arrow Articles by Anderson, S. M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2006, p. 8840-8856, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.01846-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

MDM2 Is Required for Suppression of Apoptosis by Activated Akt1 in Salivary Acinar Cells{triangledown}

Kirsten H. Limesand,1,{dagger} Kathryn L. Schwertfeger,2,{ddagger} and Steven M. Anderson1,2*

Department of Pathology,1 Program in Molecular Biology, School of Medicine, University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado 800452

Received 20 September 2005/ Returned for modification 15 October 2005/ Accepted 7 September 2006

Chronic damage to the salivary glands is a common side effect following head and neck irradiation. It is hypothesized that irreversible damage to the salivary glands occurs immediately after radiation; however, previous studies with rat models have not shown a causal role for apoptosis in radiation-induced injury. We report that etoposide and gamma irradiation induce apoptosis of salivary acinar cells from FVB control mice in vitro and in vivo; however, apoptosis is reduced in transgenic mice expressing a constitutively activated mutant of Akt1 (myr-Akt1). Expression of myr-Akt1 in the salivary glands results in a significant reduction in phosphorylation of p53 at serine18, total p53 protein accumulation, and p21WAF1 or Bax mRNA following etoposide or gamma irradiation of primary salivary acinar cells. The reduced level of p53 protein in myr-Akt1 salivary glands corresponds with an increase in MDM2 phosphorylation in vivo, suggesting that the Akt/MDM2/p53 pathway is responsible for suppression of apoptosis. Dominant-negative Akt blocked phosphorylation of MDM2 in salivary acinar cells from myr-Akt1 transgenic mice. Reduction of MDM2 levels in myr-Akt1 primary salivary acinar cells with small interfering RNA increases the levels of p53 protein and renders these cells susceptible to etoposide-induced apoptosis in spite of the presence of activated Akt1. These results indicate that MDM2 is a critical substrate of activated Akt1 in the suppression of p53-dependent apoptosis in vivo.

* Corresponding author. Mailing address: University of Colorado Health Sciences Center at Fitzsimons, Department of Pathology, P.O. Box 6511, Aurora, CO 80045. Phone: (303) 724-3742. Fax: (303) 724-3705. E-mail: Steve.Anderson{at}UCHSC.edu.

{triangledown} Published ahead of print on 18 September 2006.

{dagger} Present address: University of Arizona, Department of Nutritional Sciences, 1177 E. 4th St., Shantz Building Room 421, Tucson, AZ 85721.

{ddagger} Present address: Baylor College of Medicine, One Baylor Plaza, Department of Molecular and Cellular Biology M635, Houston, TX 77030.

Molecular and Cellular Biology, December 2006, p. 8840-8856, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.01846-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Grundmann, O., Mitchell, G.C., Limesand, K.H. (2009). Sensitivity of Salivary Glands to Radiation: from Animal Models to Therapies. JDR 88: 894-903 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»