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Oncogenic activity of BIRC2 and BIRC3 mutants independent of nuclear factor-κB-activating potential
Azusa Yamato1,2, Manabu Soda1, Toshihide Ueno1
1Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Abstract:
BIRC2 and BIRC3 are closely related members of the inhibitor of apoptosis (IAP) family of proteins and play pivotal roles in regulation of nuclear factor-κB (NF-κB) signaling and apoptosis. Copy number loss for and somatic mutation of BIRC2 and BIRC3 have been frequently detected in lymphoid malignancies, with such genetic alterations being thought to contribute to carcinogenesis through activation of the noncanonical NF-κB signaling pathway. Here we show that BIRC2 and BIRC3 mutations are also present in a wide range of epithelial tumors and that most such nonsense or frameshift mutations confer direct transforming potential. This oncogenic function of BIRC2/3 mutants is largely independent of their ability to activate NF-κB signaling. Rather, all of the transforming mutants lack an intact RING finger domain, with loss of ubiquitin ligase activity being essential for transformation irrespective of NF-κB regulation. The serine-threonine kinase NIK was found to be an important, but not exclusive, mediator of BIRC2/3-driven carcinogenesis, although this function was independent of NF-κB activation. Our data thus suggest that, in addition to the BIRC2/3-NIK-NF-κB signaling pathway, BIRC2/3-NIK signaling targets effectors other than NF-κB and thereby contributes directly to carcinogenesis. Identification of these effectors may provide a basis for the development of targeted agents for the treatment of lymphoid malignancies and other cancers with BIRC2/3 alterations.
Insights
Mutations in BIRC2 and BIRC3, previously linked to lymphoid cancers, also drive epithelial tumor development. This oncogenic function stems from loss of ubiquitin ligase activity, independent of NF-κB signaling, suggesting new therapeutic targets.
Area of Science:
- Molecular Biology
- Cancer Biology
- Signal Transduction
Background:
- BIRC2 and BIRC3 (inhibitors of apoptosis proteins) regulate NF-κB signaling and apoptosis.
- Genetic alterations in BIRC2/BIRC3 are common in lymphoid malignancies, linked to noncanonical NF-κB pathway activation and carcinogenesis.
- The precise role of BIRC2/BIRC3 mutations in epithelial tumors remains less understood.
Purpose of the Study:
- To investigate the role of BIRC2 and BIRC3 mutations in epithelial cancers.
- To elucidate the mechanisms underlying the oncogenic function of mutated BIRC2/BIRC3.
- To identify potential therapeutic targets for cancers with BIRC2/BIRC3 alterations.
Main Methods:
- Analysis of BIRC2 and BIRC3 mutations in a diverse range of epithelial tumors.
- Functional assays to assess the transforming potential of BIRC2/BIRC3 mutants.
- Investigation of the role of ubiquitin ligase activity and NF-κB signaling in BIRC2/3-mediated transformation.
- Exploration of the involvement of NIK (NF-κB-inducing kinase) in BIRC2/3-driven carcinogenesis.
Main Results:
- BIRC2 and BIRC3 mutations, including nonsense and frameshift types, were identified in various epithelial tumors.
- Most BIRC2/3 mutants exhibited direct transforming potential.
- Oncogenic function was largely independent of NF-κB activation and required loss of ubiquitin ligase activity due to an intact RING finger domain.
- NIK was identified as a key mediator, but its role in BIRC2/3-driven carcinogenesis was independent of NF-κB activation.
Conclusions:
- BIRC2/BIRC3 mutations contribute to epithelial carcinogenesis through mechanisms beyond NF-κB activation.
- Loss of ubiquitin ligase activity in BIRC2/3 mutants is critical for their oncogenic function.
- BIRC2/3-NIK signaling impacts effectors other than NF-κB, promoting cancer development.
- Targeting these pathways may offer new therapeutic strategies for cancers with BIRC2/BIRC3 alterations.
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