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Start Over Author "Gaarde WA" Journal cancer research
2 results on '"Gaarde WA"'

1. Targets of c-Jun NH(2)-terminal kinase 2-mediated tumor growth regulation revealed by serial analysis of gene expression.

Author

Potapova O, Anisimov SV, Gorospe M, Dougherty RH, Gaarde WA, Boheler KR, and Holbrook NJ

Subjects
Apoptosis drug effects, Apoptosis physiology, Blotting, Northern, Cell Cycle drug effects, Cell Cycle physiology, Cell Division physiology, Gene Expression drug effects, Gene Expression Profiling, Humans, JNK Mitogen-Activated Protein Kinases, Male, Mitogen-Activated Protein Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinases genetics, Oligonucleotides, Antisense genetics, Oligonucleotides, Antisense pharmacology, Prostatic Neoplasms pathology, Signal Transduction physiology, Mitogen-Activated Protein Kinases physiology, Prostatic Neoplasms enzymology, Prostatic Neoplasms genetics
Abstract

Although the c-Jun NH(2)-terminal kinase (JNK) pathway has been implicated in mediating cell growth and transformation, its downstream effectors remain to be identified. Using JNK2 antisense oligonucleotides (JNK2AS), we uncovered previously a role for JNK2 in regulating cell cycle progression and survival of human PC3 prostate carcinoma cells. Here, to identify genes involved in implementing JNK2-mediated effects, we have analyzed global gene expression changes in JNK2-deprived PC3 cells using Serial Analysis of Gene Expression. More than 40,000 tags each were generated from control and PC3-JNK2AS libraries, corresponding to 15,999 and 20,698 unique transcripts, respectively. Transcripts corresponding to transcription factors, stress-induced genes, and apoptosis-related genes were up-regulated in the PC3-JNK2AS library, revealing a significant stress response after the inhibition of JNK2 expression. Genes involved in DNA repair, mRNA turnover, and drug resistance were found to be down-regulated by inhibition of JNK2 expression, further highlighting the importance of JNK2 signaling in regulating cell homeostasis and tumor cell growth.

Published
2002

2. Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells.

Author

Hauck CR, Sieg DJ, Hsia DA, Loftus JC, Gaarde WA, Monia BP, and Schlaepfer DD

Subjects
Adenocarcinoma pathology, Cell Movement drug effects, Enzyme Activation, Epidermal Growth Factor pharmacology, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System physiology, Matrix Metalloproteinase 9 metabolism, Matrix Metalloproteinase Inhibitors, Mitogen-Activated Protein Kinases metabolism, Neoplasm Invasiveness, Oligonucleotides, Antisense genetics, Oligonucleotides, Antisense pharmacology, Phosphorylation, Protein-Tyrosine Kinases biosynthesis, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases physiology, Tumor Cells, Cultured, Adenocarcinoma enzymology, Cell Movement physiology, Epidermal Growth Factor antagonists & inhibitors, Protein-Tyrosine Kinases antagonists & inhibitors
Abstract

Elevated focal adhesion kinase (FAK) expression in human tumor cells has been correlated with an increased cell invasion potential. In cell culture, studies with FAK-null fibroblasts have shown that FAK function is required for cell migration. To determine the role of elevated FAK expression in facilitating epidermal growth factor (EGF)-stimulated human adenocarcinoma (A549) cell motility, antisense oligonucleotides were used to reduce FAK protein expression >75%. Treatment of A549 cells with FAK antisense (ISIS 15421) but not a mismatched control (ISIS 17636) oligonucleotide resulted in reduced EGF-stimulated p130(Cas)-Src complex formation, c-Jun NH(2)-terminal kinase (JNK) activation, directed cell motility, and serum-stimulated cell invasion through Matrigel. Because residual FAK protein in ISIS 15421-treated A549 cells was highly phosphorylated at the Tyr-397/Src homology (SH)2 binding site, expression of the FAK COOH-terminal domain (FRNK) was also used as an inhibitor of FAK function. Adenoviral-mediated infection and expression of FRNK promoted FAK dephosphorylation at Tyr-397, resulted in reduced EGF-stimulated JNK as well as extracellular-regulated kinase 2 (ERK2) kinase activation, inhibited matrix metalloproteinase-9 (MMP-9) secretion, and potently blocked both random and EGF-stimulated A549 cell motility. Equivalent expression of a FRNK (S-1034) point-mutant that did not promote FAK dephosphorylation also did not affect EGF-stimulated signaling or cell motility. Dose-dependent reduction in EGF-stimulated A549 motility was observed with the PD98059 MEK1 inhibitor and the batimastat (BB-94) inhibitor of MMP activity, but not with the SB203580 inhibitor of p38 kinase. Finally, comparisons between normal, FAK-null, and FAK-reconstituted fibroblasts revealed that FAK enhanced EGF-stimulated JNK and ERK2 kinase activation that was required for cell motility. These data indicate that FAK functions as an important signaling platform to coordinate EGF-stimulated cell migration in human tumor cells and support a role for inhibitors of FAK expression or activity in the control of neoplastic cell invasion.

Published
2001

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