C/EBPα arrests cell proliferation through direct inhibition of cdk2 and cdk4

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