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

• Published in: Journal of cellular biochemistry 2020-04, Vol.121 (4), p.2839-2850
• Main Authors: Thacker, Gatha, Mishra, Mukul, Sharma, Akshay, Singh, Anil Kumar, Sanyal, Sabyasachi, Trivedi, Arun Kumar
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Amino acids; C/EBPα; CDK2; Cyclin-dependent kinase 2; Degradation; Depletion; Deregulation; Kinases; Leukemia; myeloid differentiation; Myeloid leukemia; Phosphorylation; Proteasomes; Proteins; Tumor suppressor genes; Ubiquitin; ubiquitination
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.29516

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. Here, we demonstrate that cyclin‐dependent kinase 2 (CDK2) potentiates ubqiuitin‐mediated degradation of tumor suppressor CCAAT‐enhancer‐binding protein α (C/EBPα) leading to its functional expression in acute myeloid leukemia cells.