Wang H, Goode T, Iakova P, Albrecht JH, Timchenko NA

Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.

CCAAT/enhancer binding protein alpha (C/EBPalpha) causes growth arrest via direct interaction with the cyclin-dependent kinases cdk2 and cdk4. In this paper, we present evidence showing that C/EBPalpha enhances a proteasome-dependent degradation of cdk4 during growth arrest in liver of newborn mice and in cultured cells. Overexpression of C/EBPalpha in several biological systems leads to a reduction of cdk4 protein levels, but not mRNA levels. Experiments with several tissue culture models reveal that C/EBPalpha enhances the formation of cdk4-ubiquitin conjugates and induces degradation of cdk4 through a proteasome-dependent pathway. As a result, the half-life of cdk4 is shorter and protein levels of cdk4 are reduced in cells expressing C/EBPalpha. Gel filtration analysis of cdk4 complexes shows that a chaperone complex cdk4-cdc37-Hsp90, which protects cdk4 from degradation, is abundant in proliferating livers that lack C/EBPalpha, but this complex is weak or undetectable in livers expressing C/EBPalpha. Our studies show that C/EBPalpha disrupts the cdk4-cdc37-Hsp90 complex via direct interaction with cdk4 and reduces protein levels of cdk4 by increasing proteasome-dependent degradation of cdk4.

Mesh Terms:
Animals, Animals, Newborn, CCAAT-Enhancer-Binding Protein-alpha, COS Cells, Cell Cycle, Cell Cycle Proteins, Cells, Cultured, Cercopithecus aethiops, Chromatography, Gel, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinases, Cysteine Endopeptidases, Drosophila Proteins, Fetal Proteins, HSP90 Heat-Shock Proteins, Half-Life, Hepatocytes, Isopropyl Thiogalactoside, Lac Operon, Liver, Macromolecular Substances, Mice, Mice, Knockout, Molecular Chaperones, Multienzyme Complexes, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins, RNA, Messenger, Recombinant Fusion Proteins, Transfection, Ubiquitin

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