The proline-histidine-rich CDK2/CDK4 interaction region of C/EBPα is dispensable for C/EBPα-mediated growth regulation in vivo

The C/EBP alpha transcription factor regulates growth and differentiation of several tissues during embryonic development. Several hypotheses as to how C/EBP alpha 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/EBP alpha 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(Delta PHR/Delta PHR) (Delta PHR) 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 Delta PHR 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 Delta PHR mice and their control littermates. These in vivo data demonstrate that any C/EBP alpha-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/EBP alpha null fetal livers yielded similar results.