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SUMO modification of Sam68 enhances its ability to repress cyclin D1 expression and inhibits its ability to induce apoptosis

Oncogene volume 25, pages 4955–4964 (2006)Cite this article

Abstract

Sam68 (Src associated in mitosis; 68 kDa) is an RNA-binding protein and substrate of Src family kinases. It is thought to play a role in cell cycle progression. Overexpression of Sam68 in fibroblasts was reported to have two separable functions dependent on its ability to bind RNA — cell cycle arrest or the induction of apoptosis. Post-translational modification with SUMO (small ubiquitin-like modifier) is common to many transcription factors and can regulate protein localization, stability and function. Here we show Sam68 to be modified by SUMO, and demonstrate that the SUMO E3 ligase (PIAS1) (protein inhibitor of activated STAT1) can enhance Sam68 sumoylation. Lysine 96, the first lysine in the amino-terminal region of Sam68, was found to be the major SUMO acceptor site. Mutation of the SUMO acceptor lysine to arginine enhanced the ability of Sam68 to induce apoptosis but inhibited its ability to act as a transcriptional inhibitor of cyclin D1 expression. A SUMO-1 Sam68 fusion protein, on the other hand, inhibited the ability of Sam68 to induce apoptosis but was a strong repressor of cyclin D1 expression. Thus, SUMO may be an important regulator of Sam68 function in cell cycle progression.

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Acknowledgements

We thank Kim Orth for the HA-SUMO expression constructs, Jiann-an Tan for the PIAS1 expression construct and Karl Riabowol for cyclin D1 promoter luciferase reporter. We thank Laurie Robertson for her assistance with flow cytometry and cell sorting. This work was supported by grants to DJF from the Canadian Breast Cancer Research Alliance and the Canadian Breast Cancer Foundation (AB/NWT Chapter). IB was supported by a Canadian Institutes of Health Research (CIHR) Doctoral Research Award and an Alberta Heritage Foundation for Medical Research (AHFMR) Studentship Award.

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  1. I Babic

    Present address: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA

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  1. Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada

    I Babic, E Cherry & D J Fujita

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Correspondence to D J Fujita.

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Babic, I., Cherry, E. & Fujita, D. SUMO modification of Sam68 enhances its ability to repress cyclin D1 expression and inhibits its ability to induce apoptosis. Oncogene 25, 4955–4964 (2006). https://doi.org/10.1038/sj.onc.1209504

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