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      C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4.

      Molecular Cell
      Amino Acid Sequence, Animals, CCAAT-Enhancer-Binding Protein-alpha, genetics, metabolism, CDC2-CDC28 Kinases, Cell Division, physiology, Cell Fractionation, Cell Line, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinases, antagonists & inhibitors, chemistry, Enzyme Inhibitors, Genes, Reporter, Liver, Mice, Mice, Knockout, Molecular Sequence Data, Nuclear Proteins, Protein Structure, Secondary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Rats, Recombinant Fusion Proteins

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          Abstract

          The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) is a strong inhibitor of cell proliferation. We found that C/EBPalpha directly interacts with cdk2 and cdk4 and arrests cell proliferation by inhibiting these kinases. We mapped a short growth inhibitory region of C/EBPalpha between amino acids 175 and 187. This portion of C/EBPalpha is responsible for direct inhibition of cyclin-dependent kinases and causes growth arrest in cultured cells. C/EBPalpha inhibits cdk2 activity by blocking the association of cdk2 with cyclins. Importantly, the activities of cdk4 and cdk2 are increased in C/EBPalpha knockout livers, leading to increased proliferation. Our data demonstrate that the liver-specific transcription factor C/EBPalpha brings about growth arrest through direct inhibition of cdk2 and cdk4.

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