Decorin inhibits macrophage colony-stimulating factor proliferation of macrophages and enhances cell survival through induction of p27(Kip1) and p21(Waf1).
Decorin is a small proteoglycan that is ubiquitous in the extracellular matrix of mammalian tissues. It has been extensively demonstrated that decorin inhibits tumor cell growth; however, no data have been reported on the effects of decorin in normal cells. Using nontransformed macrophages from bone marrow, results of this study showed that decorin inhibits macrophage colony-stimulating factor (M-CSF)-dependent proliferation by inducing blockage at the G(1) phase of the cell cycle without affecting cell viability. In addition, decorin rescues macrophages from the induction of apoptosis after growth factor withdrawal. Decorin induces the expression of the cdk inhibitors p21(Waf1) and p27(Kip1). Using macrophages from mice where these genes have been disrupted, inhibition of proliferation mediated by decorin is related to p27(Kip1) expression, whereas p21(Waf1) expression is necessary to protect macrophages from apoptosis. Decorin also inhibits M-CSF-dependent expression of MKP-1 and extends the kinetics of ERK activity, which is characteristic when macrophages become activated instead of proliferating. The effect of decorin on macrophages is not due to its interaction with epidermal growth factor or interferon-gamma receptors. Furthermore, decorin increases macrophage adhesion to the extracellular matrix, and this may be partially responsible for the expression of p27(Kip1) and the modification of ERK activity, but not for the increased cell survival.
Xaus
J
J
Departament de Fisiologia (Biologia del Macròfag), Facultat de Biologia and Fundació August Pi i Sunyer, Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain.
Comalada
M
M
Cardó
M
M
Valledor
A F
AF
Celada
A
A
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism*; D058575:Decorin; D004347:Drug Interactions; D066246:ErbB Receptors; D016326:Extracellular Matrix Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D011509:Proteoglycans / Q000494:pharmacology*; D017471:Receptors, Interferon; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism*; D000096743:Interferon gamma Receptor
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D058575:Decorin; D066246:ErbB Receptors; D016326:Extracellular Matrix Proteins; D016173:Macrophage Colony-Stimulating Factor; D011509:Proteoglycans; D017471:Receptors, Interferon; D025521:Tumor Suppressor Proteins; D000096743:Interferon gamma Receptor; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; C546879:Dcn protein, mouse