Polyomavirus Middle T Antigen Induces the Transcription of Osteopontin, a Gene Important for the Migration of Transformed Cells

Abstract

Middle T antigen (MT) is the principal oncoprotein of murine polyomavirus. Experiments on the acute immediate effects of MT expression on cellular RNA levels showed that expression of osteopontin (OPN) was strongly induced by MT expression. Osteopontin is a protein known to be associated with cancer. It has a role in tumor progression and invasion. Protein analysis confirmed that MT induced the secretion of OPN into the extracellular medium. Expression of antisense OPN RNA had no effect on the growth of MT-transformed cells. However, it had a strong effect on the ability of MT transformants to migrate or to fill a wound. Analysis of MT mutants implicated both the SHC and phosphatidylinositol 3-kinase pathways in OPN induction. Reporter assays showed that MT regulated the OPN promoter through two of its PEA3 (polyoma enhancer activator 3) sites. As critical PEA3 sites are also part of the polyomavirus enhancer, the same signaling important for viral replication also contributes to virally induced metastatic potential.