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Abstract
Like other KCTD proteins, KCTD15 is involved in important albeit distinct biological processes as cancer, neural crest formation, and obesity. Here, we characterized the role of KCTD15 in different physiological/pathological states to gain insights into its diversified function(s). The silencing of KCTD15 in MLL-rearranged leukemia models induced attenuation of the NF-κB pathway associated with a downregulation of pIKK-β and pIKB-α. Conversely, the activation of peripheral blood T cells upon PMA/ionomycin stimulation remarkably upregulated KCTD15 and, simultaneously, pIKK-β and pIKB-α. Moreover, a significant upregulation of KCTD15 was also observed in CD34 hematopoietic stem/progenitor cells where the NF-κB pathway is physiologically activated. The association between KCTD15 upregulation and increased NF-κB signaling was confirmed by luciferase assay as well as KCTD15 and IKK-β proximity ligation and immunoprecipitation experiments. The observed upregulation of IKK-β by KCTD15 provides a novel and intriguing interpretative key for understanding the protein function in a wide class of physiological/pathological conditions ranging from neuronal development to cancer and obesity/diabetes.
Highlights
IntroductionWe have found that KCTD15, a member of the emerging family of the KCTD (potassium channel tetramerization domain) proteins[8], is upregulated in patients and cell lines of both childhoods B-cell ALL9 and A ML10
We have recently shown that KCTD15 is strongly upregulated in B cell acute lymphoblastic/lymphoid leukemia (ALL) (B-ALL), the molecular mechanism underlying a potential action of this protein in the pathology is yet to be e lucidated[9]
Starting from our recent observation that KCTD15 is upregulated in both B-ALL9 and acute myeloid leukemia (AML) cell lines[10] and patient-derived samples, we here found an intriguing link between the upregulation of the protein and the activation of the NF-κB pathway that was observed in different contexts and conditions
Summary
We have found that KCTD15, a member of the emerging family of the KCTD (potassium channel tetramerization domain) proteins[8], is upregulated in patients and cell lines of both childhoods B-cell ALL9 and A ML10 This protein displays a characteristic and well-defined profile of expression in peripheral blood cells (granulocytes, monocytes, and lymphocytes), suggesting that it plays an active role in both physiological and pathological processes, the mechanism underlying this activity is yet to be uncovered. In the present manuscript, starting from the analysis of the transcriptome of the peripheral blood of healthy individuals and leukemia patients, we highlighted the possibility that KCTD15 could be involved in the NF-κB signaling This hypothesis was corroborated by several experiments that demonstrate the involvement of KCTD15 into the activation of the IKβ kinase (IKK-β) enzyme complex initiating a cascade of events that trigger the NF-κB pathway.
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