p73 is a growth-regulated protein in vascular smooth muscle cells and is present at high levels in human atherosclerotic plaque.
p73 is a newly described homologue of the tumour suppressor p53 that was cloned serendipitously and subsequently shown to possess considerable homology in the most evolutionarily conserved p53 domains. Yet despite the fact that p53 and p73 have extensive structural similarities, their functions are proving to be quite different. We now show that p73 is a growth-regulated protein in the vasculature, being markedly increased in cultured vascular smooth muscle (VSM) cells stimulated with 10% serum, with no significant change in p73 mRNA levels. Stability of p73 is increased after serum stimulation and, probably contributing to this increase in p73 stability, the c-Abl oncogene protein displays a higher molecular weight species and is probably phosphorylated and activated in serum-stimulated VSM cells. The serum-mediated induction of p73 is not altered when the cells are incubated with inhibitors of the MAP/ERK pathway or tyrosine kinases, and is not stimulated by PDGF-BB, demonstrating that the mechanism of the increase in p73 does not involve this classical receptor tyrosine kinase growth factor signalling cascade. p73 is markedly increased in plaque tissue taken from atherosclerotic human carotid arteries, but not in comparable intimal scrapings from normal human arteries. Our data indicate that the tumour suppressor homologue p73 probably plays a role in VSM cell cycle progression, being mediated by a specific, as yet unidentified, serum component, and identifies a new function for this protein as being important in the pathogenesis of human atherosclerosis as well as other vascular diseases.
Weiss
R H
RH
Division of Nephrology, Department of Internal Medicine, University of California, Davis, 95616, USA. rhweiss@ucdavis.edu
Howard
L L
LL
D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D000077214:Becaplermin; D016227:Benzoquinones; D002460:Cell Line; D003470:Culture Media; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D047029:Lactams, Macrocyclic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D017828:Rifabutin / Q000031:analogs & derivatives; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D016227:Benzoquinones; D003470:Culture Media; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006133:Growth Substances; D047029:Lactams, Macrocyclic; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011809:Quinones; D012333:RNA, Messenger; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000077214:Becaplermin; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one