C/EBPα triggers proteasome-dependent degradation of cdk4 during growth arrest

Hongmei Wang, Triona Goode, Polina Iakova, Jeffrey H. Albrecht, Nikolai A. Timchenko

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


CCAAT/enhancer binding protein alpha (C/EBPα) causes growth arrest via direct interaction with the cyclin-dependent kinases cdk2 and cdk4. In this paper, we present evidence showing that C/EBPα enhances a proteasome-dependent degradation of cdk4 during growth arrest in liver of newborn mice and in cultured cells. Overexpression of C/EBPα 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/EBPα 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/EBPα. 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/EBPα, but this complex is weak or undetectable in livers expressing C/EBPα. Our studies show that C/EBPα disrupts the cdk4-cdc37-Hsp90 complex via direct interaction with cdk4 and reduces protein levels of cdk4 by increasing proteasome-dependent degradation of cdk4.

Original languageEnglish (US)
Pages (from-to)930-941
Number of pages12
JournalEMBO Journal
Issue number5
StatePublished - Mar 1 2002


  • C
  • Cdk4
  • Cell cycle
  • EBPα
  • Proteasome


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