IBtk? Activates the ?-Catenin-Dependent Transcription of MYC through Ubiquitylation and Proteasomal Degradation of GSK3? in Cancerous B Cells.

The IBTK gene encodes the IBtk? protein that is a substrate receptor of E3 ubiquitin ligase, Cullin 3. We have previously reported the pro-tumorigenic activity of Ibtk in MYC-dependent B-lymphomagenesis observed in E?-myc transgenic mice. Here, we provide mechanistic evidence of the functional interplay between IBtk? and MYC. We show ...
that IBtk?, albeit indirectly, activates the ?-catenin-dependent transcription of the MYC gene. Of course, IBtk? associates with GSK3? and promotes its ubiquitylation, which is associated with proteasomal degradation. This event increases the protein level of ?-catenin, a substrate of GSK3?, and results in the transcriptional activation of the MYC and CCND1 target genes of ?-catenin, which are involved in the control of cell division and apoptosis. In particular, we found that in Burkitt's lymphoma cells, IBtk? silencing triggered the downregulation of both MYC 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 IBtk? interactome and highlight IBtk? as a potential novel therapeutic target to be employed in the strategy for personalized therapy of B cell lymphoma.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Cell Line, Tumor, Cells, Cultured, Cyclin D1, Glycogen Synthase Kinase 3 beta, HEK293 Cells, Humans, Lymphoma, B-Cell, Mice, Proteasome Endopeptidase Complex, Proteolysis, Proto-Oncogene Proteins c-myc, Ubiquitination, beta Catenin
Int J Mol Sci
Date: Feb. 12, 2022
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