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The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb

Oncogene volume 38, pages 1080–1092 (2019)Cite this article

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Abstract

Overexpression of the oncogene MYBL2 (B-Myb) is associated with increased cell proliferation and serves as a marker of poor prognosis in cancer. However, the mechanism by which B-Myb alters the cell cycle is not fully understood. In proliferating cells, B-Myb interacts with the MuvB core complex including LIN9, LIN37, LIN52, RBBP4, and LIN54, forming the MMB (Myb–MuvB) complex, and promotes transcription of genes required for mitosis. Alternatively, the MuvB core interacts with Rb-like protein p130 and E2F4–DP1 to form the DREAM complex that mediates global repression of cell cycle genes in G0/G1, including a subset of MMB target genes. Here, we show that overexpression of B-Myb disrupts the DREAM complex in human cells, and this activity depends on the intact MuvB-binding domain in B-Myb. Furthermore, we found that B-Myb regulates the protein expression levels of the MuvB core subunit LIN52, a key adapter for assembly of both the DREAM and MMB complexes, by a mechanism that requires S28 phosphorylation site in LIN52. Given that high expression of B-Myb correlates with global loss of repression of DREAM target genes in breast and ovarian cancer, our findings offer mechanistic insights for aggressiveness of cancers with MYBL2 amplification, and establish the rationale for targeting B-Myb to restore cell cycle control.

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Acknowledgements

We thank James DeCaprio and Iain Morgan for critically reading the manuscript, and Sophia Gruszecki for technical support. This project was supported in part by R01CA188571 (L.L.), R01CA132685 and R01GM124148 (S.M.R.), and F30CA221004 (A.N.I.).

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Authors and Affiliations

  1. Division of Hematology, Oncology and Palliative Care and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Audra N. Iness, Jessica Felthousen, Varsha Ananthapadmanabhan, Fatmata Sesay, Siddharth Saini & Larisa Litovchick

  2. Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064, USA

    Keelan Z. Guiley & Seth M. Rubin

  3. Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Mikhail Dozmorov

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  1. Audra N. Iness
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Correspondence to Larisa Litovchick.

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Iness, A.N., Felthousen, J., Ananthapadmanabhan, V. et al. The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb. Oncogene 38, 1080–1092 (2019). https://doi.org/10.1038/s41388-018-0490-y

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