Cells in vivo and in vitro from osteopetrotic mice homozygous for c-src disruption show suppression of synthesis of osteopontin, a multifunctional extracellular matrix protein.
Mice carrying homozygous disruption of the c-src proto-oncogene (Src-/-) develop osteopetrosis due to an impaired ability of osteoclasts to adhere to the bone surface and/or to form bone-resorbing ruffled border. It has also been reported that osteopontin (OPN), a secreted phosphoprotein, mediates osteoclast adherence to the bone matrix. We report here that cells from Src-/- mice, both in vitro and in vivo, express OPN mRNA and protein at a significantly reduced level as compared to cells from Src+/- and +/+ animals, suggesting a potential role for the proto-oncogene c-src in the regulation of OPN gene expression. Our data also show that OPN gene expression can be induced by treatment of SR-/- cells with epidermal growth factor (EGF) and 12-O-tetradecanoyl phorbol-13-acetate (TPA). Results obtained from studies using inhibitors of receptor tyrosine kinases (RTKs) and protein kinase C (PKC) suggest that PKC and RTK are positioned in a pathway with PKC as the downstream effector for the EGF-induced OPN gene expression in SRC-/- cells, and that pp60c-src and EGF may regulate OPN gene expression through a common signalling pathway. Furthermore, contrary to published reports, our study shows that EGF-mediated cell signalling does not require functional interaction between the EGF-receptor and pp60c-src.
Chackalaparampil
I
I
Department of Biology, McGill University, Montreal, Quebec, Canada.
Peri
A
A
Nemir
M
M
Mckee
M D
MD
Lin
P H
PH
Mukherjee
B B
BB
Mukherjee
A B
AB
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D016227:Benzoquinones; D001842:Bone and Bones / Q000648:ultrastructure; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D017931:DNA Primers; D004261:DNA Replication / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D015870:Gene Expression / Q000187:drug effects; D006720:Homozygote; D047029:Lactams, Macrocyclic; D051379:Mice; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010022:Osteopetrosis / Q000235:genetics / Q000473:pathology*; D053495:Osteopontin; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors
D016227:Benzoquinones; D017931:DNA Primers; D047029:Lactams, Macrocyclic; D011809:Quinones; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D017828:Rifabutin; D004815:Epidermal Growth Factor; C020754:herbimycin; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate