Targeted disruption of the inosine 5'-monophosphate dehydrogenase type I gene in mice.
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.
Gu
Jing Jin
JJ
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Tolin
Amy K
AK
Jain
Jugnu
J
Huang
Hai
H
Santiago
Lalaine
L
Mitchell
Beverly S
BS
D000818:Animals; D002455:Cell Division / Q000235:genetics; D005260:Female; D018390:Gene Targeting; D005818:Genetic Engineering / Q000379:methods; D006147:Guanine / Q000096:biosynthesis; D006160:Guanosine Triphosphate / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007168:IMP Dehydrogenase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015847:Interleukin-4; D007527:Isoenzymes / Q000235:genetics; D008214:Lymphocytes / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D007527:Isoenzymes; D020033:Protein Isoforms; D015847:Interleukin-4; D006147:Guanine; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; C463299:IMPDH1, mouse; D007041:Hypoxanthine Phosphoribosyltransferase