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

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.

Cyclin G2 upregulation impairs migration, invasion, and network formation through RNF123/Dvl2/JNK signaling in the trophoblast cell line HTR8/SVneo, a possible role in preeclampsia

“…[66][67][68] Furthermore, the CCNG2 and PP2A complex has been demonstrated to mediate the inactivation of CDK2 and activation of CDK4 through dephosphorylation of either Rb or p107. 4,69 It is worth mentioning that both CDK2 and CDK4 are involved in the modulation of some critical transcription factors; with CDk2 being responsible for regulating the forkhead box O1 (FOXO1), 70 CCAAT-enhancer-binding protein α (C/EBPα), 71 and MYBL2, 72 while CDK4 being responsible for regulating the E2F, 73 aristaless-related homeobox protein (ARX), 74 and forkhead box O3 (FOXO3). 75 We hereby prove that CCNG2 F I G U R E 7 Hypothetical model for CCNG2's inhibition of JNK-dependent Wnt/PCP signaling.…”

Acute Myeloid Leukemia-Related Proteins Modified by Ubiquitin and Ubiquitin-like Proteins

“…CDK2 regulates the cell cycle and influences diverse biological processes including DNA damage, intracellular transport, protein degradation, and signal transduction [ 66 ]. Inhibition of CDK2 downregulates SCF Skp2 and stabilizes the C/EBPα protein expression [ 76 ]. CDK2 phosphorylates and stabilizes SCF Skp2 , which in turn promotes ubiquitination and degradation of C/EBPα [ 77 ].…”

“…CDK2 downregulates wild-type, isoform, and phospho-deficient mutants of C/EBPα [ 76 ]. CDK2 also inhibits its transactivation potential and cellular functions [ 76 ].…”

“…CDK2 downregulates wild-type, isoform, and phospho-deficient mutants of C/EBPα [ 76 ]. CDK2 also inhibits its transactivation potential and cellular functions [ 76 ]. It appears that CDK2 phosphorylates a few Ub E3 ligases of C/EBPα, which subsequently degrade it [ 76 ].…”

“…CDK2 also inhibits its transactivation potential and cellular functions [ 76 ]. It appears that CDK2 phosphorylates a few Ub E3 ligases of C/EBPα, which subsequently degrade it [ 76 ]. Among the several CDKs, CDK2 is specifically degraded through ubiquitin-dependent proteasome degradation during AML cell differentiation [ 128 ].…”