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

Gatha Thacker, Mukul Mishra, Akshay Sharma, Anil Kumar Singh, Sabyasachi Sanyal, Arun Kumar Trivedi

Journal of cellular biochemistry 2020 Apr

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Deregulation and functional inhibition of CCAAT-enhancer-binding protein α (C/EBPα), 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/EBPα protein levels in myeloid leukemia cells. The overexpression of CDK2 inhibited C/EBPα both in a heterologous HEK293T and U937 myeloid leukemia cells. On the contrary, CDK2 depletion enhanced endogenous C/EBPα protein levels. CDK2 mitigated C/EBPα levels by promoting its ubiquitin-mediated proteasome degradation. We further showed that although CDK2 interacted with C/EBPα, direct interaction of CDK2 with C/EBPα is not involved in C/EBPα downregulation. CDK2-dependent phosphorylation of C/EBPα on its widely reported phosphorylatable amino acid residues is apparently not required for C/EBPα degradation by CDK2. Furthermore, our data demonstrate that CDK2-driven C/EBPα inhibition mitigates its transactivation potential and cellular functions such as ability to promote myeloid differentiation and growth arrest. © 2019 Wiley Periodicals, Inc.

Citation

Gatha Thacker, Mukul Mishra, Akshay Sharma, Anil Kumar Singh, Sabyasachi Sanyal, Arun Kumar Trivedi. CDK2 destabilizes tumor suppressor C/EBPα expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia. Journal of cellular biochemistry. 2020 Apr;121(4):2839-2850