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Molecular and Cellular Biology, February 2006, p. 1028-1037, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.1028-1037.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Proline-Histidine-Rich CDK2/CDK4 Interaction Region of C/EBP{alpha} Is Dispensable for C/EBP{alpha}-Mediated Growth Regulation In Vivo

Bo Torben Porse,1,2* Thomas Åskov Pedersen,3 Marie Sigurd Hasemann,1,2 Mikkel Bruhn Schuster,1,2 Peggy Kirstetter,3 Tom Luedde,3 Inge Damgaard,1,2 Elke Kurz,3 Charlotte Karlskov Schjerling,2 and Claus Nerlov3

Section for Gene Therapy Research,1 Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark,2 Mouse Biology Unit, European Molecular Biology Laboratory, 00016 Monterotondo, Italy3

Received 22 June 2005/ Returned for modification 3 August 2005/ Accepted 4 November 2005

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.

* Corresponding author. Mailing address: Section for Gene Therapy Research, Department of Clinical Biochemistry, Copenhagen University Hospital, Juliane Maries Vej 20-9322, DK2100 Copenhagen, Denmark. Phone: 45-3545-6011. Fax: 45-3546-6727. E-mail: porse{at}rh.dk.

Molecular and Cellular Biology, February 2006, p. 1028-1037, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.1028-1037.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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