Disruption of c-Jun Reduces Cellular Migration and Invasion through Inhibition of c-Src and Hyperactivation of ROCK II Kinase

Abstract

The spread of metastatic tumors to different organs is associated with poor prognosis. The metastatic process requires migration and cellular invasion. The protooncogene c-jun encodes the founding member of the activator protein-1 family and is required for cellular proliferation and DNA synthesis in response to oncogenic signals and plays an essential role in chemical carcinogenesis. The role of c-Jun in cellular invasion remains to be defined. Genetic deletion of c-Jun in transgenic mice is embryonic lethal; therefore, transgenic mice encoding a c-Jun gene flanked by LoxP sites (c-junf/f) were used. c-jun gene deletion reduced c-Src expression, hyperactivated ROCK II signaling, and reduced cellular polarity, migration, and invasiveness. c-Jun increased c-Src mRNA abundance and c-Src promoter activity involving an AP-1 site in the c-Src promoter. Transduction of c-jun−/− cells with either c-Jun or c-Src retroviral expression systems restored the defective cellular migration of c-jun−/− cells. As c-Src is a critical component of pathways regulating proliferation, survival, and metastasis, the induction of c-Src abundance, by c-Jun, provides a novel mechanism of cooperative signaling in cellular invasion.

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

“…For example, AP-1 can act synergistically with AP-4 to activate SV40 late gene transcription (41,42). A component of AP-1 the oncoprotein c-jun has been shown to be hyperactivated by JNK in epithelial cells (43). Our observations showing JNK involvement in the regulation of AP-4 activity following IGF-1 stimulation are supported by a study wherein AP-4 was shown to be downregulated by glucocorticoids (44).…”

c-Jun Induces Mammary Epithelial Cellular Invasion and Breast Cancer Stem Cell Expansion

“…Transgenic Mice, Expression Plasmids, and Promoter Cloning-Transgenic animals carrying floxed c-jun alleles, c-jun f/f , and the MMTV-ErbB2 transgenic mice were previously described (12,26,27). All experimental procedures performed using these mice were approved by the Institutional Animal Care and Use Committee (IACUC) of Thomas Jefferson University.…”

“…The retroviral expression plasmid encoding Cre was cloned through the insertion of the cDNA from the vector pMC-Cre-PGK-Hyg (from Dr. P. Stanley) as an EcoRI fragment into the retroviral expression plasmid pMSCV-IRES-GFP (30). Expression of Cre from pMSCV-IRES-GFP vector was confirmed by Western blot using an antibody directed to Cre (MMS-106) (12). The EcoRI fragment of the rat c-Jun DNA (31) was subcloned into the retroviral expression vector MSCV-IRES-GFP to form MSCV-c-Jun-IRES-GFP.…”

“…Analysis of mice embryo fibroblasts (MEFs) 2 derived from either c-jun Ϫ/Ϫ or c-jun f/f mice identified a role for c-Jun in regulating expression of the epidermal growth factor receptor, cellular proliferation, and migration (11,12). c-jun Ϫ/Ϫ MEFs undergo premature senescence associated with a proliferative defect due to the induction of p53/p21 CIP1 (13,14).…”

NF-κB Activation, Dependent on Acetylation/Deacetylation, Contributes to HIF-1 Activity and Migration of Bone Metastatic Breast Carcinoma Cells

“…The level of c-Src transducer is elevated in the most aggressive breast carcinomas (29), and seems to regulate NF-κB activity, to increase HDAC3 phosphorylation and to affect HDAC3 nuclear translocation, which may also depend on a decrease in interaction with IκBα (30)(31)(32). c-Src overexpression, which is sometimes c-Jun dependent, may represent a system regulating cell migration (33). HDACs function as corepressors/coactivators of transcription factors by means of as yet unclear mechanisms, although HDAC3 is a corepressor of NF-κB through the deacetylation of p65 (34,35).…”