TY - JOUR
T1 - A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells
AU - Pakay, J. L.
AU - Diesch, J.
AU - Gilan, O.
AU - Yip, Y. Y.
AU - Sayan, E.
AU - Kolch, W.
AU - Mariadason, J. M.
AU - Hannan, R. D.
AU - Tulchinsky, E.
AU - Dhillon, A. S.
PY - 2012/4/5
Y1 - 2012/4/5
N2 - 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.
AB - 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.
KW - cancer
KW - ERK
KW - Fra-1
KW - RAS
KW - TBP-1
KW - turnover
UR - http://www.scopus.com/inward/record.url?scp=84859611380&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859611380&partnerID=8YFLogxK
U2 - 10.1038/onc.2011.375
DO - 10.1038/onc.2011.375
M3 - Article
C2 - 21874050
AN - SCOPUS:84859611380
VL - 31
SP - 1817
EP - 1824
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 14
ER -