CDK2 destabilizes tumor suppressor C/EBPα expression through ubiquitin‐mediated proteasome degradation in acute myeloid leukemia. Issue 4 (6th November 2019)

• Record Type: Journal Article
• Authors: Thacker, Gatha; Mishra, Mukul; Sharma, Akshay; Singh, Anil Kumar; Sanyal, Sabyasachi; Trivedi, Arun Kumar
• Is Part Of: Journal of cellular biochemistry. Volume 121:Issue 4(2020)
• Page Start: 2839
• Page End: 2850
• Publication Date: 2019-11-06
• Subjects: acute myeloid leukemia -- C/EBPα -- CDK2 -- myeloid differentiation -- ubiquitination; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.29516
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: 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. Abstract : 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.