The proline-histidine-rich CDK2/CDK4 interaction region of C/EBPalpha is dispensable for C/EBPalpha-mediated growth regulation in vivo.
The C/EBPalpha transcription factor regulates growth and differentiation of several tissues during embryonic development. Several hypotheses as to how C/EBPalpha inhibits cellular growth in vivo have been derived, mainly from studies of tissue culture cells. In fetal liver it has been proposed that a short, centrally located, 15-amino-acid proline-histidine-rich region (PHR) of C/EBPalpha is responsible for the growth-inhibitory function of the protein through its ability to interact with CDK2 and CDK4, thereby inhibiting their activities. Homozygous Cebpa(DeltaPHR/DeltaPHR) (DeltaPHR) mice, carrying a modified cebpa allele lacking amino acids 180 to 194, were born at the Mendelian ratio, reached adulthood, and displayed no apparent adverse phenotypes. When fetal livers from the DeltaPHR mice were analyzed for their expression of cell cycle markers, bromodeoxyuridine incorporation, cyclin-dependent kinase 2 kinase activity, and global gene expression, we failed to detect any cell cycle or developmental differences between the DeltaPHR mice and their control littermates. These in vivo data demonstrate that any C/EBPalpha-mediated growth repression via the PHR as well as the basic region is dispensable for proper embryonic development of, and cell cycle control in, the liver. Surprisingly, control experiments performed in C/EBPalpha null fetal livers yielded similar results.
Porse
Bo Torben
BT
Section for Gene Therapy Research, Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark. porse@rh.dk
Pedersen
Thomas Askov
TA
Hasemann
Marie Sigurd
MS
Schuster
Mikkel Bruhn
MB
Kirstetter
Peggy
P
Luedde
Tom
T
Damgaard
Inge
I
Kurz
Elke
E
Schjerling
Charlotte Karlskov
CK
Nerlov
Claus
C
D017667:Adipocytes / Q000166:cytology; D000595:Amino Acid Sequence; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D006639:Histidine / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008099:Liver / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D011392:Proline / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary; D051381:Rats; D017384:Sequence Deletion
D022763:CCAAT-Enhancer-Binding Protein-alpha; D006639:Histidine; D011392:Proline; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4