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A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells
journal contribution
posted on 2022-11-29, 22:57 authored by J L Pakay, J Diesch, O Gilan, Y Y Yip, E Sayan, W Kolch, J M Mariadason, R D Hannan, E Tulchinsky, Amardeep DhillonAmardeep DhillonFos-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. © 2012 Macmillan Publishers Limited All rights reserved.
History
Journal
OncogeneVolume
31Pagination
1817 - 1824Publisher DOI
ISSN
0950-9232eISSN
1476-5594Publication classification
C1 Refereed article in a scholarly journal; C1.1 Refereed article in a scholarly journalUsage metrics
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