Poster Presentation 25th Lorne Cancer Conference 2013

A PR55α-containing PP2A complex positively regulates Fra-1/c-Jun function in tumour cells (#184)

Omer Gilan 1 , Kathy Jastzrebski 1 , Nikki Verrills 2 , Jeannine Diesch 1 , Ross D Hannan 1 , Amardeep S Dhillon 1
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Biochemistry, Newcastle University, Newcastle, NSW, Australia

The Activator Protein-1 (AP-1) transcription factor complex regulates gene expression downstream of signal transduction pathways activated by a variety of growth factors, cytokines, hormones and cellular stresses. The products of AP-1-regulated genes are required for the execution of fundamental cellular processes, including proliferation, survival and differentiation. AP-1 complexes consist of a dimeric core, formed mainly by members of the Fos, Jun and ATF protein families.

The Fos related antigen-1 (Fra-1) is a Fos family protein that is frequently over-expressed in cancers and regulates key processes involved in cancer progression, including cell migration and invasion. However, the mechanism(s) whereby Fra-1 regulates these processes remains unclear. We hypothesized that a better understanding of these issues could be gained through analysis of the Fra-1/AP-1 interactome in CRC cells, given the pervasive role that protein-protein interactions play in transcriptional regulation.

A proteomic screen for such interactions in highly invasive CRC cells revealed Fra-1 associates with a heterotrimeric protein phosphatase 2A (PP2A) complex consisting of a catalytic subunit (PP2Acat), the PR65a scaffold, and the PR55a regulatory subunit. The latter demonstrated preferential binding to Fra-1/c-Jun but not c-Fos/c-Jun dimers, and was required for recruitment of PP2Acat to the AP-1 complexes. Silencing PR55α resulted in the down-regulation of Fra-1/c-Jun target gene expression and the migratory and invasive potential of CRC cells. This positive regulation of Fra-1/c-Jun function appeared to largely involve PR55a/PP2Acat-mediated dephosphorylation of Thr239 in c-Jun, which enhanced Fra-1/c-Jun target gene binding. Collectively, our findings identify PR55α/PP2A as a key regulator of AP-1-mediated transciption of pro-invasive/EMT-associated genes in tumour cells.