Role of the isoforms of CCAAT/enhancer-binding protein in the initiation of phosphoenolpyruvate carboxykinase (GTP) gene transcription at birth.
The gene for phosphoenolpyruvate carboxykinase (PEPCK), a target of CCAAT/enhancer-binding protein-alpha (C/EBPalpha) and -beta (C/EBPbeta), begins to be expressed in the liver at birth. Mice homozygous for a deletion in the gene for CEBPalpha (C/EBPalpha-/- mice) die shortly after birth of hypoglycemia, with no detectable hepatic PEPCK mRNA and negligible hepatic glycogen stores. Half of the mice homozygous for a deletion in the gene for CEBPbeta (C/EBPbeta-/- mice) have normal glucose homeostasis (phenotype A), and the other half die at birth of hypoglycemia due to a failure to express the gene for PEPCK and to mobilize hepatic glycogen (phenotype B). Insulin deficiency induces C/EBPalpha and PEPCK gene transcription in the livers of 19-day fetal rats, whereas dibutyryl cyclic AMP (Bt2cAMP) increases the expression of the gene for C/EBPbeta and causes a transient burst of PEPCK mRNA. Bt2cAMP induces PEPCK mRNA in the livers of fetal C/EBPalpha-/- mice, but at only 20% of the level of control animals; however, there is no induction of PEPCK mRNA if the cyclic nucleotide is injected into C/EBPalpha-/- mice immediately after delivery. The expression of the gene for C/EBPbeta is markedly induced in the livers of C/EBPalpha-/- mice within 2 h after the administration of Bt2cAMP. C/EBPbeta-/- mice injected at 20 days of fetal life with Bt2cAMP have a normal pattern of induction of hepatic PEPCK mRNA. In C/EBPbeta-/- mice with phenotype B, the administration of Bt2cAMP immediately after delivery induces PEPCK mRNA, causes the mobilization of hepatic glycogen, and maintains normal glucose homeostasis for up to 4 h (duration of the experiment). We conclude that C/EBPalpha is required for the cAMP induction of PEPCK gene expression in the liver and that C/EBPbeta can compensate for the loss of C/EBPalpha if its concentration is induced to appropriate levels.
Croniger
C
C
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935, USA.
Trus
M
M
Lysek-Stupp
K
K
Cohen
H
H
Liu
Y
Y
Darlington
G J
GJ
Poli
V
V
Hanson
R W
RW
Reshef
L
L
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008099:Liver / Q000196:embryology / Q000201:enzymology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D003994:Bucladesine; D019764:Phosphoenolpyruvate Carboxykinase (ATP)