The role of p21-activated kinase 3 (PAK3) in activating protein 1 (AP-1) induced oncogenesis

Activating protein 1 (AP-1) is a fundamental transcription factor that plays a role in cell proliferation, differentiation and apoptosis. Little is known about the role of the diverse downstream targets of the active AP-1 complex, a dimer comprising of the Jun, Fos or ATF bZIP-domain proteins. Deregulation of AP-1 has been linked to many cancers, with its over-expression leading to the transformation of normal cells. Previous studies utilizing a doxycycline-inducible cJun/AP-1 construct identified PAK3, a serine/threonine kinase signal transduction molecule, as a potential AP-1-target involved in the AP-1 characteristic transformation. PAK3 has been implicated in a variety of pathological disorders and over-expression of other PAK-family members has been linked to certain cancers. This project aims to investigate the role of PAK3 in cJun/AP-1 induced oncogenesis. Quantitative RT-PCR and Western Blot Analysis showed elevated PAK3 expression at both the mRNA and protein level in cJun-overexpressing cells. PAK3 expression levels were also elevated in transformed human and cancer cell lines compared to normal cells. Analysis of the PAK3 promoter using promoter luciferase assays identified a putative AP-1 binding site, at position +52 to +60, which may be responsible for the increased PAK3 promoter activity in response to cJun/AP-1 over-expression. siRNA inhibition of the PAK3 protein showed the regression of the morphological phenotype and migratory potential associated with cJun-transformed cells. However PAK3 inhibition showed no significant effect on the proliferative response of cJun-transformed cells. This study suggests a potential regulation of cJun/AP-1 on PAK3 as well as a role for PAK3 in AP-1 induced transformation; specifically that associated with cell morphology and migration.