CDK2 destabilizes tumor suppressor C/EBPα expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia

Deregulation and functional inhibition of CCAAT-enhancer-binding protein alpha (C/EBP alpha), a key transcription factor of myeloid lineage leads to development of myeloid leukemia. In this study, we show that cyclin-dependent kinase 2 (CDK2) negatively regulates C/EBP alpha protein levels in myeloid leukemia cells. The overexpression of CDK2 inhibited C/EBP alpha both in a heterologous HEK293T and U937 myeloid leukemia cells. On the contrary, CDK2 depletion enhanced endogenous C/EBP alpha protein levels. CDK2 mitigated C/EBP alpha levels by promoting its ubiquitin-mediated proteasome degradation. We further showed that although CDK2 interacted with C/EBP alpha, direct interaction of CDK2 with C/EBP alpha is not involved in C/EBP alpha downregulation. CDK2-dependent phosphorylation of C/EBP alpha on its widely reported phosphorylatable amino acid residues is apparently not required for C/EBP alpha degradation by CDK2. Furthermore, our data demonstrate that CDK2-driven C/EBP alpha inhibition mitigates its transactivation potential and cellular functions such as ability to promote myeloid differentiation and growth arrest.