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Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms

Oncogene volume 18, pages 3564–3573 (1999)Cite this article

Abstract

The tumor suppressor Bin1 was identified through its interaction with the N-terminal region of Myc which harbors its transcriptional activation domain. Here we show that Bin1 and Myc physically and functionally associate in cells and that Bin1 inhibits cell proliferation through both Myc-dependent and Myc-independent mechanisms. Bin1 specifically inhibited transactivation by Myc as assayed from artificial promoters or from the Myc target genes ornithine decarboxylase (ODC) and α prothymosin (pT). Inhibition of ODC but not pT required the presence of the Myc binding domain (MBD) of Bin1 suggesting two mechanisms of action. Consistent with this possibility, a non-MBD region of Bin1 was sufficient to recruit a repression function to DNA that was unrelated to histone deacetylase. Regions outside the MBD required for growth inhibition were mapped in Ras cotransformation or HepG2 hepatoma cell growth assays. Bin1 required the N-terminal BAR domain to suppress focus formation by Myc whereas the C-terminal U1 and SH3 domains were required to inhibit adenovirus E1A or mutant p53, respectively. All three domains contributed to Bin1 suppression of tumor cell growth but BAR-C was most crucial. These findings supported functional interaction between Myc and Bin1 in cells and indicated that Bin1 could inhibit malignant cell growth through multiple mechanisms.

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Acknowledgements

We thank Roberto Buccafusca for technical assistance, John Cleveland for the ODCΔluc reporter plasmid, Michael Cole for a murine c-Myc baculovirus, Chi Dang for GAL4-Myc plasmids, and Karl Munger for HPV E7 and control vectors. For discussion and critical comments, we thank Shelley Berger, Frank Rauscher III, and members of our laboratory. This work was supported by grants from the ACS and US Army Breast Cancer Research Program. Katherine Elliott was supported by an NIH Training Grant. George C Prendergast is a Pew Scholar in the Biomedical Sciences.

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Author notes

  1. Katherine Elliott and Daitoku Sakamuro: K Elliott and D Sakamuro contributed equally to this study

Authors and Affiliations

  1. The Wistar Institute, 3601 Spruce Street, Philadelphia, 19104, Pennsylvania, USA

    Katherine Elliott, Daitoku Sakamuro, Amithaba Basu, Wei Du, William Wunner & George C Prendergast

  2. Institute for Molecular Biology and Tumour Research (IMT), Universitaet Marburg, Emil-Mankopffstrasse 2, Marburg, 35033, Germany

    Peter Staller, Stefan Gaubatz & Martin Eilers

  3. Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Pittsburgh, 15213, Pennsylvania, USA

    Hong Zhang & Edward Prochownik

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  1. Katherine Elliott
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Elliott, K., Sakamuro, D., Basu, A. et al. Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms. Oncogene 18, 3564–3573 (1999). https://doi.org/10.1038/sj.onc.1202670

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