4.7 Article

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

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出版社

MDPI
DOI: 10.3390/ijms23042044

关键词

MYC; beta-catenin; GSK3 beta; Burkitt's lymphoma; IBtk alpha

资金

  1. MIUR-PRIN [2017MHJJ55_002]
  2. EU [PONAIM18970041]
  3. [POR FES/FESR 2014-20-ATS ALCMEONE cup J18C17000610006]

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The IBTK gene encodes the IBtk alpha protein, which plays a role in the regulation of MYC-dependent B-lymphomagenesis. Mechanistically, IBtk alpha indirectly activates the beta-catenin-dependent transcription of the MYC gene by modulating GSK3 beta. Silencing IBtk alpha leads to downregulation of MYC expression and increased apoptosis in Burkitt's lymphoma cells.
The IBTK gene encodes the IBtk alpha 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 mu-myc transgenic mice. Here, we provide mechanistic evidence of the functional interplay between IBtk alpha and MYC. We show that IBtk alpha, albeit indirectly, activates the beta-catenin-dependent transcription of the MYC gene. Of course, IBtk alpha associates with GSK3 beta and promotes its ubiquitylation, which is associated with proteasomal degradation. This event increases the protein level of beta-catenin, a substrate of GSK3 beta, and results in the transcriptional activation of the MYC and CCND1 target genes of beta-catenin, which are involved in the control of cell division and apoptosis. In particular, we found that in Burkitt's lymphoma cells, IBtk alpha 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 alpha interactome and highlight IBtk alpha as a potential novel therapeutic target to be employed in the strategy for personalized therapy of B cell lymphoma.

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