Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis.
In many malignant cells, both the anchorage requirement for survival and the function of the p53 tumor suppressor gene are subverted. These effects are consistent with the hypothesis that survival signals from extracellular matrix (ECM) suppress a p53-regulated cell death pathway. We report that survival signals from fibronectin are transduced by the focal adhesion kinase (FAK). If FAK or the correct ECM is absent, cells enter apoptosis through a p53-dependent pathway activated by protein kinase C lambda/iota and cytosolic phospholipase A2. This pathway is suppressible by dominant-negative p53 and Bcl2 but not CrmA. Upon inactivation of p53, cells survive even if they lack matrix signals or FAK. This is the first report that p53 monitors survival signals from ECM/FAK in anchorage- dependent cells.
Ilić
D
D
Departments of Stomatology and Anatomy, University of California San Francisco, San Francisco, California 94143-0512, USA.
Almeida
E A
EA
Schlaepfer
D D
DD
Dazin
P
P
Aizawa
S
S
Damsky
C H
CH
D000818:Animals; D017302:Annexins / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D001798:Blood Proteins / Q000494:pharmacology; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004727:Endothelium / Q000166:cytology; D005109:Extracellular Matrix / Q000737:chemistry / Q000201:enzymology*; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D005353:Fibronectins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases; D049452:Green Fluorescent Proteins; D020287:In Situ Nick-End Labeling; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000378:metabolism; D008164:Luminescent Proteins; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013583:Synovial Membrane / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017302:Annexins; D001798:Blood Proteins; D015815:Cell Adhesion Molecules; D016895:Culture Media, Serum-Free; D005353:Fibronectins; D007202:Indicators and Reagents; D007527:Isoenzymes; D008164:Luminescent Proteins; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; C087857:protein kinase C gamma; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D020169:Caspases