Enhanced cell motility and invasion of chicken embryo fibroblasts in response to JUN over‐expression

Abstract

Malignant tumor cells exhibit a number of distinct properties involved not only with deregulated cell proliferation but also enhanced migration and invasion. The Jun oncogene has been well studied in regard to its role in cell proliferation. Many of the target genes deregulated by Jun encode matrix metalloproteases (MMPs) such as MMP1, MMP3 and MMP9. These targets implicate a prominent role for Jun in tumor cell invasion, in addition to its role in growth transformation. To investigate this possibility, we have examined the effect of over-expression of transforming and non-transforming versions of Jun on motility and invasion of chicken embryo fibroblasts (CEFs). We found that over-expression of either form of Jun results in elevated intrinsic cellular motility as well as increased motility in response to several different chemoattractants, including 3T3-conditioned media, basic fibroblast growth factor, hepatocyte growth factor and Matrigel. The capacity of these cells to invade through Matrigel is also elevated as a result of Jun over-expression. In addition to these effects, CEFs expressing Jun secrete factors that stimulate the motility of a human tongue carcinoma cell line. Our results suggest that Jun plays an important role in the potentiation of cell motility and invasion through multiple mechanisms. Int.

A Splice Variant of CD99 Increases Motility and MMP-9 Expression of Human Breast Cancer Cells through the AKT-, ERK-, and JNK-dependent AP-1 Activation Signaling Pathways

“…Transformation with oncogenic forms of Fos or Jun proteins makes normal rat fibroblast cells invasive (48,69), but dominant-negative mutants and antisense oligonucleotides for AP-1 component genes inhibit the invasion and migration of oncogenic AP-1-transformed and growth factor-stimulated fibroblasts (48,70,71). Overexpression of c-JUN induces the invasiveness of chick embryo fibroblasts and MCF-7 breast cancer cells (72,73). FosB and Fra-1 were also shown to increase the invasiveness and motility of MCF-7 and MDA-MB-231 breast cancer cells (74,75).…”

Transcription factors control invasion: AP-1 the first among equals

“…Fos transformants also differentially express genes that directly regulate the cytoskeleton, including the actin binding protein ezrin and members of the tropomyosin family (Joos and Muller, 1995). Putative Jun targets are also implicated in the invasive phenotype, including the matrix metalloproteinases MMP1, MMP3 and MMP9 (Bos et al, 1999), the ECM associated protein osteonectin/SPARC (Briggs et al, 2002) the protein kinase C substrate SSeCKS (Cohen et al, 2001) and the motility and angiogenic factor, autotaxin (Black et al, 2004). Consistent with these observations, v-fos transformed cells are constitutively invasive in a three-dimensional in vitro invasion assay, indicating that AP-1 activity, in the form of v-Fos expression, is sufficient for invasion in this system (Hennigan et al, 1994).…”

“…Expression of v-Fos in Src transformed cells enhances their mobility in vitro (Taniguchi et al, 1989). Chicken embryo fibroblasts transformed by v-Jun also have enhanced motility and invasion (Bos et al, 1999) as are human MCF-7 breast carcinoma cells overexpressing c-Jun (Rinehart-Kim et al, 2000). Conditional expression of an ER-Fos fusion protein induces mesenchymal to epithelial transition and invasion in murine breast epithelial cells (Reichmann et al, 1992), a property that is shared by c-Jun and Fra-1 (Fialka et al, 1996;Kustikova et al, 1998).…”

TAF4b and Jun/Activating Protein-1 Collaborate to Regulate the Expression of Integrin α6 and Cancer Cell Migration Properties

“…Different types of tumors have been related to RAS-protein activation, which in turn, regulate the activity of AP-1 (20). For instance, c-Jun, which is frequently implicated in the acquisition of invasive properties in aggressive forms of cancer (21), is required for in vitro cellular transformation by oncogenic RAS partially via a phosphorylation mechanism (22,23).…”