Type V collagen is an epithelial cell cycle inhibitor that is induced by and mimics the effects of transforming growth factor beta1.
The regulation of epithelial cell cycle progression by extracellular matrix proteins was investigated in mink lung epithelial cells (Mv1Lu cells) and primary human keratinocytes. Exogenous type V collagen was able to mimic all of the inhibitory effects of type 1 transforming growth factor beta (TGF-beta1). No significant inhibitory effect was observed with collagen types I, III, and IV; laminin; or fibronectin. The type V collagen used was not contaminated with TGF-betas. TGF-beta1 increased the rate of type V collagen protein secretion in Mv1Lu cells, which occurred coincident with DNA synthesis inhibition. Both TGF-beta1 and type V collagen inhibited retinoblastoma protein phosphorylation and the expression of cyclin-dependent kinase (cdk) 4 and cdk2, but not p27Kip expression. Mv1Lu cells constitutively expressing the SV40 T antigen or cdk4 were resistant to the inhibitory effects of both TGF-beta1 and type V collagen. Our results demonstrate that type V collagen is a novel and specific epithelial cell cycle inhibitor and suggest that it may act as an autocrine mediator of the inhibitory effects of TGF-beta1.
Parekh
T V
TV
Preclinical Oncology Discovery, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA.
Wang
X W
XW
Makri-Werzen
D M
DM
Greenspan
D S
DS
Newman
M J
MJ
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D008907:Mink; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D003094:Collagen; D004247:DNA; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases