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Activation of the Notch-regulated transcription factor CBF1/RBP-Jkappa through the 13SE1A oncoprotein
S Ansieau1, L J Strobl, A Leutz
1Max-Delbrueck-Centrum für Molekulare Medizin, 13122 Berlin, Germany.
Abstract:
Signaling through the Notch pathway controls cell growth and differentiation in metazoans. Following binding of its ligands, the intracellular part of the cell surface Notch1 receptor (Notch1-IC) is released and translocates to the nucleus, where it alters the function of the DNA-binding transcription factor CBF1/RBP-Jkappa. As a result, CBF1/RBP-Jkappa is converted from a repressor to an activator of gene transcription. Similarly, the Epstein Barr viral oncoprotein EBNA2, which is required for B-cell immortalization, activates genes through CBF1. Moreover, the TAN-1 and int-3 oncogenes represent activated versions of Notch1 and Notch4, respectively. Here, we show that the adenoviral oncoprotein 13S E1A also binds to CBF1/RBP-Jkappa, displaces associated corepressor complexes, and activates CBF1/RBP-Jkappa-dependent gene expression. Our results suggest that the central role of the Notch-CBF1/RBP-Jkappa signaling pathway in cell fate decisions renders it susceptible to pathways of viral replication and oncogenic conversion.
Insights
Adenoviral oncoprotein 13S E1A binds to CBF1/RBP-Jkappa, a key factor in Notch signaling. This interaction activates gene expression, suggesting viral proteins can hijack cell fate pathways for replication and oncogenesis.
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncology
Background:
- The Notch signaling pathway regulates crucial cellular processes like growth and differentiation in multicellular organisms.
- Notch1 receptor activation leads to nuclear translocation of its intracellular domain (Notch1-IC), converting the transcription factor CBF1/RBP-Jkappa from a repressor to an activator.
- Viral oncoproteins, such as Epstein-Barr virus's EBNA2, also utilize CBF1/RBP-Jkappa for B-cell immortalization.
Purpose of the Study:
- To investigate the interaction between adenoviral oncoprotein 13S E1A and the CBF1/RBP-Jkappa transcription factor.
- To determine if 13S E1A can modulate CBF1/RBP-Jkappa-dependent gene expression.
- To explore the implications of this interaction in viral replication and oncogenesis.
Main Methods:
- Co-immunoprecipitation assays to detect binding between 13S E1A and CBF1/RBP-Jkappa.
- Reporter gene assays to assess the activation of CBF1/RBP-Jkappa-dependent promoters.
- Analysis of corepressor complex displacement from CBF1/RBP-Jkappa.
Main Results:
- Adenoviral 13S E1A directly binds to CBF1/RBP-Jkappa.
- 13S E1A binding leads to the displacement of associated corepressor complexes.
- This interaction results in the activation of CBF1/RBP-Jkappa-dependent gene expression.
Conclusions:
- The adenoviral oncoprotein 13S E1A hijacks the Notch-CBF1/RBP-Jkappa signaling pathway.
- Viral manipulation of this pathway facilitates viral replication and contributes to oncogenic transformation.
- The central role of Notch signaling in cell fate makes it a target for viral oncogenes.