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A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

Oncogene volume 31, pages 1817–1824 (2012)Cite this article

Abstract

Fos-related antigen-1 (Fra-1) is a member of the Activator Protein-1 (AP-1) transcription factor superfamily that is overexpressed in a variety of cancers, including colon, breast, lung, bladder and brain. High Fra-1 levels are associated with enhanced cell proliferation, survival, migration and invasion. Despite its frequent overexpression, the molecular mechanisms that regulate the accumulation of Fra-1 proteins in tumour cells are not well understood. Here, we show that turnover of Fra-1, which does not require ubiquitylation, is cooperatively regulated by two distinct mechanisms—association with the 19S proteasomal subunit, TBP-1, and by a C-terminal degron, which acts independently of TBP-1, but is regulated by RAS–ERK (extracellular signal-regulated kinase) signalling. TBP-1 depletion stabilized Fra-1 and further increased its levels in tumour cells expressing RAS–ERK pathway oncogenes. These effects correlated with increased AP-1 transcriptional activity. We suggest that during Fra-1 degradation, association with TBP-1 provides a mechanism for ubiquitin-independent proteasomal recognition, while the C terminus of the protein regulates its subsequent proteolytic processing.

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Article Open access 16 December 2023

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Acknowledgements

We thank Drs Nishida, Satoh, Greer and Gillespie for generously providing reagents used in this study, and Dr Willie Bienvenut for assistance with the mass spectrometry experiments. This work was supported by grants from the National Health and Medical Research Council of Australia (to ASD and RDH) and the Association for International Cancer Research (to ET).

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  1. J L Pakay and J Diesch: These authors made equal contributions to this work

Authors and Affiliations

  1. Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, Victoria, Australia

    J L Pakay, J Diesch, O Gilan, Y-Y Yip & R D Hannan

  2. Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK

    E Sayan & E Tulchinsky

  3. Systems Biology Ireland, University College Dublin, Dublin, Ireland

    W Kolch

  4. Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria, Australia

    J M Mariadason

  5. Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    J Diesch, O Gilan, R D Hannan & A S Dhillon

  6. Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

    R D Hannan

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Correspondence to E Tulchinsky or A S Dhillon.

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Pakay, J., Diesch, J., Gilan, O. et al. A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells. Oncogene 31, 1817–1824 (2012). https://doi.org/10.1038/onc.2011.375

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