p53 suppresses Src-induced podosome and rosette formation and cellular invasiveness through the upregulation of caldesmon.
The tumor-suppressive role of p53 at the level of tumor initiation is well documented. It has also been shown previously that p53 acts against tumor progression/metastasis. However, its role in modulating cell migration and invasion leading to metastasis is poorly understood. In this study, using vascular smooth muscle cells and NIH 3T3 fibroblast cells, we have shown that p53 potently suppresses Src-induced podosome/rosette formation, extracellular matrix digestion, cell migration, and invasion. The overexpression of exogenous wild-type p53 or the activation of the endogenous p53 function suppresses, while the short hairpin RNA-mediated knockdown of p53 expression or the pageing of its function exacerbates, Src-induced migratory and invasive phenotypes. We have also found that p53 expression and function are downregulated in cells stably transformed with constitutively active Src that exhibit aggressive invasive properties. Lastly, p53 upregulates the expression of caldesmon, an actin-binding protein that has been shown to be an inhibitor of podosome/invadopodium formation. The ability of p53 to suppress Src phenotypes in transformed cells was largely abolished by knocking down caldesmon. This study reports a novel molecular mechanism (caldesmon), as well as a structural basis (podosomes/rosettes), to show how p53 can act as an anti-motility/invasion/metastasis agent.
Department of Biochemistry, Queen's University, Kingston, ON, Canada.
Utpal K
UK
Mukhopadhyay
Robert
R
Eves
Lilly
L
Jia
Patrick
P
Mooney
Alan S
AS
Mak
D000818:Animals; D001808:Blood Vessels / Q000166:cytology; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D041681:NIH 3T3 Cells; D011509:Proteoglycans / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011554:Pseudopodia / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
D002148:Calmodulin-Binding Proteins; D004338:Drug Combinations; D007797:Laminin; D008840:Microfilament Proteins; D011509:Proteoglycans; D016159:Tumor Suppressor Protein p53; C059485:matrigel; D003094:Collagen; D016392:Proto-Oncogene Proteins pp60(c-src); D013755:Tetradecanoylphorbol Acetate