title: A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells.
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.
authors.affiliation: Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: J L
authors.initials: JL
authors.lastname: Pakay
authors.forename: J
authors.initials: J
authors.lastname: Diesch
authors.forename: O
authors.initials: O
authors.lastname: Gilan
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Yip
authors.forename: E
authors.initials: E
authors.lastname: Sayan
authors.forename: W
authors.initials: W
authors.lastname: Kolch
authors.forename: J M
authors.initials: JM
authors.lastname: Mariadason
authors.forename: R D
authors.initials: RD
authors.lastname: Hannan
authors.forename: E
authors.initials: E
authors.lastname: Tulchinsky
authors.forename: A S
authors.initials: AS
authors.lastname: Dhillon
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D009369:Neoplasms / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D018631:ras Proteins; D000099169:Fos-Related Antigen 1; C064757:PSMC3 protein, human