IBtkα Activates the β-Catenin-Dependent Transcription of through Ubiquitylation and Proteasomal Degradation of GSK3β in Cancerous B Cells.

The gene encodes the IBtkα protein that is a substrate receptor of E3 ubiquitin ligase, Cullin 3. We have previously reported the pro-tumorigenic activity of in -dependent B-lymphomagenesis observed in transgenic mice. Here, we provide mechanistic evidence of the functional interplay between IBtkα and . We show that IBtkα, albeit indirectly, activates the β-catenin-dependent transcription of the gene. Of course, IBtkα associates with GSK3β and promotes its ubiquitylation, which is associated with proteasomal degradation. This event increases the protein level of β-catenin, a substrate of GSK3β, and results in the transcriptional activation of the and target genes of β-catenin, which are involved in the control of cell division and apoptosis. In particular, we found that in Burkitt's lymphoma cells, IBtkα silencing triggered the downregulation of both mRNA and protein expression, as well as a strong decrease of cell survival, mainly through the induction of apoptotic events, as assessed by using flow cytometry-based cell cycle and apoptosis analysis. Collectively, our results shed further light on the complex puzzle of IBtkα interactome and highlight IBtkα as a potential novel therapeutic target to be employed in the strategy for personalized therapy of B cell lymphoma.