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Degradation of B-Myb by ubiquitin-mediated proteolysis: involvement of the Cdc34-SCFp45Skp2 pathway

Oncogene volume 19, pages 2986–2995 (2000)Cite this article

Abstract

B-Myb, a highly conserved member of the Myb oncoprotein family, is a 110 kDa sequence-specific DNA binding protein expressed in virtually all proliferating cells. B-myb expression reaches its maximum at the G1/S phase boundary and during the S phase of the cell cycle. We have previously shown that B-Myb activity is cell cycle regulated and it is controlled by the antagonistic effects of cyclin D1 and A. Here we show that ectopic expression of cyclin A causes a pronounced reduction of B-Myb protein level. We provide evidence that in addition to triggering B-Myb activity an important effect of cyclin A is to facilitate multiple ubiquitination of B-Myb. The C-terminal domain of B-Myb is of key importance in mediating this effect of cyclin A. Contrary to full-length B-Myb, a C-terminal deletion mutant displays activity irrespective of cyclin A expression, does not undergo ubiquitination, and its half-life is not affected by cyclin A. Ectopic expression of either Cdc34 or the F-box protein p45Skp2, respectively the E2 and E3 components of a ubiquitination pathway that regulates the G1/S transition, accelerates degradation of B-Myb. We show that B-Myb physically and functionally interacts with components of the Cdc34-SCFp45Skp2 ubiquitin pathway and propose that B-Myb degradation may be required for controlling the correct alternation of events during progression through the cell division cycle.

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Acknowledgements

We would like to thank Dr F Hofmann for helpful suggestions and Drs G Draetta (Milano, Italy), D Bohmann (Heidelberg, Germany), W Krek (Basel, Switzerland), J Mestan (Basel, Switzerland) for providing reagents and C Genisset for technical assistance. We are also indebted to Drs S Kozma, F Hofmann and T O'Reilly for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Oncology, Novartis Pharma AG, Klybeckstrasse 141, 4057 Basel, Switzerland

    S Charrasse, I Carena, V Brondani & S Ferrari

  2. Institute of Biochemistry, University of Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany

    K-H Klempnauer

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  1. S Charrasse
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  2. I Carena
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  3. V Brondani
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  4. K-H Klempnauer
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Charrasse, S., Carena, I., Brondani, V. et al. Degradation of B-Myb by ubiquitin-mediated proteolysis: involvement of the Cdc34-SCFp45Skp2 pathway. Oncogene 19, 2986–2995 (2000). https://doi.org/10.1038/sj.onc.1203618

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