MCB
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
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 Gu, J. J.
Right arrow Articles by Mitchell, B. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gu, J. J.
Right arrow Articles by Mitchell, B. S.

 Previous Article

Molecular and Cellular Biology, September 2003, p. 6702-6712, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6702-6712.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeted Disruption of the Inosine 5'-Monophosphate Dehydrogenase Type I Gene in Mice

Jing Jin Gu,1 Amy K. Tolin,1,2,{dagger} Jugnu Jain,3 Hai Huang,1,{ddagger} Lalaine Santiago,1 and Beverly S. Mitchell1,2,4,5*

Lineberger Comprehensive Cancer Center,1 Curriculum in Genetics and Molecular Biology,2 Department of Medicine,4 Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina,5 Cell Biology and Immunology, Vertex Pharmaceuticals Inc., Cambridge, Massachusetts3

Received 4 March 2003/ Returned for modification 10 April 2003/ Accepted 16 June 2003

Inosine 5'-monophosphate dehydrogenase (IMPDH) is the critical, rate-limiting enzyme in the de novo biosynthesis pathway for guanine nucleotides. Two separate isoenzymes, designated IMPDH types I and II, contribute to IMPDH activity. An additional pathway salvages guanine through the activity of hypoxanthine-guanine phosphoribosyltransferase (HPRT) to supply the cell with guanine nucleotides. In order to better understand the relative contributions of IMPDH types I and II and HPRT to normal biological function, a mouse deficient in IMPDH type I was generated by standard gene-targeting techniques and bred to mice deficient in HPRT or heterozygous for IMPDH type II. T-cell activation in response to anti-CD3 plus anti-CD28 antibodies was significantly impaired in both single- and double-knockout mice, whereas a more general inhibition of proliferation in response to other T- and B-cell mitogens was observed only in mice deficient in both enzymes. In addition, IMPDH type I-/- HPRT-/0 splenocytes showed reduced interleukin-4 production and impaired cytolytic activity after antibody activation, indicating an important role for guanine salvage in supplementing the de novo synthesis of guanine nucleotides. We conclude that both IMPDH and HPRT activities contribute to normal T-lymphocyte activation and function.


* Corresponding author. Mailing address: 22-044 LCCC, CB#7295, University of North Carolina, Chapel Hill, NC 27599. Phone: (919) 966-5720. Fax: (919) 966-8212. E-mail: mitchell{at}med.unc.edu.

{dagger} Present address: TransTech Pharma, High Point, NC 27265.

{ddagger} Present address: Center for Demographic Studies, Duke University, Durham, N.C.


Molecular and Cellular Biology, September 2003, p. 6702-6712, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6702-6712.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.




This article has been cited by other articles:




Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
J. Bacteriol. J. Virol. Eukaryot. Cell
Microbiol. Mol. Biol. Rev. Clin. Vaccine Immunol. All ASM Journals

Copyright © 2003 by the American Society for Microbiology. All rights reserved.