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

J. L. Pakay, J. Diesch, O. Gilan, Y. Y. Yip, E. Sayan, W. Kolch, J. M. Mariadason, R. D. Hannan, E. Tulchinsky, A. S. Dhillon

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1817-1824
Number of pages8
JournalOncogene
Volume31
Issue number14
DOIs
Publication statusPublished - Apr 5 2012
Externally publishedYes

Keywords

  • cancer
  • ERK
  • Fra-1
  • RAS
  • TBP-1
  • turnover

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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