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SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells

Oncogene volume 22, pages 2443–2451 (2003)Cite this article

Abstract

p130 is a member of the retinoblastoma family of pocket proteins, which includes pRB and p107. Unlike pRB and p107, p130 protein levels decrease dramatically following its hyperphosphorylation starting in the mid-G1 phase of the cell cycle. However, the mechanism leading to p130 downregulation is unknown. We have found that the proteasome inhibitor, lactacystin, inhibited p130 downregulation in T98G cells progressing through the G1/S transition and S phase and that p130 is multiubiquitylated in 293 cells. We have previously shown that ectopic expression of both cyclin D and E induces phosphorylation and downregulation of p130. Since the SKP1/Cul1/SKP2 E3 ubiquitin ligase complex mediates ubiquitylation of substrates previously phosphorylated by cyclin-dependent kinases, we investigated the potential role of this ubiquitin ligase in mediating p130 downregulation. We found that p130 interacts with SKP1, Cul-1 and SKP2 in human 293 cells. We also found that ectopic coexpression of SKP2 and p130 leads to dose-dependent downregulation of p130, reduces p130 protein half-life and induces p130 ubiquitylation in these cells. Moreover, adenoviral-mediated expression of SKP2 accelerates downregulation of endogenous hyperphosphorylated p130 in mitogen-stimulated T98G cells and primary WI38 fibroblasts. We conclude that p130 is a substrate of the SCFSKP2 ubiquitin ligase and this E3 ligase regulates p130 abundance during the cell cycle.

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Acknowledgements

We thank Willhem Krek and Jeffry Albrecht for providing recombinant adenoviruses and plasmids, Ed Harlow for antibodies and D Bohmann for the HA-ubiquitin construct. We thank Ana Limón for initial observations and useful discussions. We thank Renée Marshall, Elena Sotillo and Dominic Salerno for critically reading the manuscript, Rosemary Dillon for manuscript editing and May Truongcao for technical assistance. JC was partially supported by fellowships from Dirección General de Investigación Científica y Técnica (Ministerio de Educación y Cultura, Spain). This work was supported in part by grants to XG including a grant from the National Institute of General Medical Sciences (NIH-R29, GM54894), a grant (NIH R01, AI45450) and a Career Development Award (K02 AI01823) from the National Institute of Allergy and Infectious Diseases and a WW Smith grant (A9802/9901). Facilities used for this work were supported in part by a Shared Resources for Cancer Research Grant R24 (CA88261-01).

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Authors and Affiliations

  1. Fels Institute for Cancer Research and Molecular Biology and Department of Biochemistry, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, 19140, PA, USA

    Sabyasachi Bhattacharya, Judit Garriga, Joaquim Calbó, Thomas Yong, Dale S Haines & Xavier Graña

  2. Department of Biochemistry and Molecular Biology, University of Barcelona, Spain

    Joaquim Calbó

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  1. Sabyasachi Bhattacharya
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Correspondence to Xavier Graña.

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Bhattacharya, S., Garriga, J., Calbó, J. et al. SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Oncogene 22, 2443–2451 (2003). https://doi.org/10.1038/sj.onc.1206339

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