Abstract
Activating Protein 1 (AP-1) plays a vital role in cell proliferation, differentiation and apoptosis. While de-regulation of AP-1 has been linked to many cancers, little is known regarding its downstream transcriptional targets that associate with cellular transformation. Previous studies identified PAK3, a serine/threonine kinase, as a potential AP-1 target gene. PAK3 has been implicated in a variety of pathological disorders and over-expression of other PAK-family members has been linked to cancer. In this study, we investigate AP-1 regulation of PAK3 expression and the role of PAK3 in cJun/AP-1-associated cellular transformation. Our results showed elevated PAK3 expression at both the mRNA and protein level in cJun-over-expressing Rat1a fibroblasts, as well as in transformed human fibroblasts. Elevated PAK3 expression in cJun/AP-1 over-expressing cells associated with a significant increase in PAK3 promoter activation. This increased promoter activity was lost when a single putative Jun binding site, which can bind AP-1 directly both in vitro and in vivo, was mutated. Further, inhibition of PAK3 using siRNA showed a regression in the cell morphology, migratory potential and actin organisation associated with AP-1 transformed cells. Our study is a first to describe a role for AP-1 in regulating PAK3 expression and suggest that PAK3 is an AP-1 target required for actin organization and migration observed in transformed cells.
Highlights
Activating Protein 1 (AP-1) regulates the expression of genes involved in cell proliferation, differentiation and apoptosis, regulating the cellular physiology in response to many stresses [1;2]
We report that cJun/AP-1 regulates elevated p21-Activated Kinase 3 (PAK3) expression by directly binding to the PAK3 promoter, and PAK3 expression is required for cell migration and actin organization in transformed fibroblasts
Our results show that PAK3 mRNA (Fig. 1A & B) and protein levels (Fig. 1C & D) were found to be significantly elevated in response to induced cJun/AP-1 expression in both growth conditions
Summary
Activating Protein 1 (AP-1) regulates the expression of genes involved in cell proliferation, differentiation and apoptosis, regulating the cellular physiology in response to many stresses [1;2]. Due to the diverse role that AP-1 plays within the cell, it is thought there is a subset of its target genes whose deregulation is vital for the maintenance of the transformed phenotype [12]. A limited number of genes have been identified to play a partial role in AP-1 associated transformation; including a hairpin-binding epidermal growth factor (HB-EGF) [13], a scaffold protein, SSeCKS [12;14] and an extra cellular matrix protein, SPARC [14;15]. A previous study using differential display and microarray analysis identified p21-Activated
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
