Mammary gland-specific ablation of focal adhesion kinase reduces the incidence of p53-mediated mammary tumour formation.

Background: Elevated expression of focal adhesion kinase (FAK) occurs in numerous human cancers including colon-, cervix- and breast cancer. Although several studies have implicated FAK in mammary tumour formation induced by ectopic oncogene expression, evidence supporting a role for FAK in spontaneous mammary tumour development caused by loss of tumour suppressor genes such as p53 is lacking. Alterations in the tumour suppressor gene p53 have been implicated in over 50% of human breast cancers.

Sensitive DsRed fluorescence-based reporter cell systems for genotoxicity and oxidative stress assessment.

Various in vitro test systems have been developed for genotoxic risk assessment in early drug development. However, these genotoxicity tests often show limited specificity, and provide limited insights into the mode of toxicity of the tested compounds. To identify genes that could serve as specific biomarkers for genotoxicity or oxidative stress, we exposed mouse embryonic stem (ES) cells to various genotoxic and oxidative stress-inducing compounds and performed genome-wide expression profiling.

Annexin A2 phosphorylation mediates cell scattering and branching morphogenesis via cofilin Activation.

Dynamic remodeling of the actin cytoskeleton is required for cell spreading, motility, and migration and can be regulated by tyrosine kinase activity. Phosphotyrosine proteomic screening revealed phosphorylation of the lipid-, calcium-, and actin-binding protein annexin A2 (AnxA2) at Tyr23 as a major event preceding ts-v-Src kinase-induced cell scattering. Expression of the phospho-mimicking mutant Y23E-AnxA2 itself was sufficient to induce actin reorganization and cell scattering in MDCK cells.

Proteomic analysis of alternative protein tyrosine phosphorylation in 1,2-dichlorovinyl-cysteine-induced cytotoxicity in primary cultured rat renal proximal tubular cells.

Toxicant exposure affects the activity of various protein tyrosine kinases. Using phosphotyrosine proteomics, we identified proteins that were differentially phosphorylated before renal cell detachment and apoptosis. Treatment of primary cultured rat proximal tubular epithelial cells with the model nephrotoxicant S-(1,2-dichlorovinyl)-L-cysteine (DCVC) resulted in early reorganization of F-actin stress fibers and formation of lamellipodia, which was followed by cell detachment from the matrix and apoptosis.

Focal adhesion kinase and protein kinase B cooperate to suppress doxorubicin-induced apoptosis of breast tumor cells.

Focal adhesion kinase (FAK) is up-regulated in a variety of cancers, including breast cancer, in association with poor disease prognosis. In the present study, we examined the role of FAK in the control of anticancer drug-induced apoptosis of mammary adenocarcinoma MTLn3 cells. Doxorubicin caused the formation of well defined focal adhesions and stress fibers early after treatment, which was later followed by their loss in association with the onset of apoptosis.