Overexpression of cyclin D1 contributes to malignancy by up-regulation of fibroblast growth factor receptor 1 via the pRB/E2F pathway.
Overexpression of cyclin D1 due to gene rearrangement, gene amplification, or simply increased transcription occurs frequently in several types of human cancers. However, overexpression of cyclin D1 in cell culture system is insufficient, by itself, to cause malignant transformation. In the present study, we found that when rodent fibroblasts that overexpress cyclin D1, but not normal fibroblasts, were treated with basic fibroblast growth factor (bFGF), there was enhanced cell cycle progression, extracellular signal-regulated kinase 2 activation, induction of anchorage-independent growth, and enhanced invasion of a Matrigel barrier. These enhanced responses to bFGF appear to be due to increased expression of fibroblast growth factor receptor 1, at both the mRNA and protein levels, in the cyclin D1-overexpressing cells. We obtained evidence that this increase in fibroblast growth factor receptor 1 expression is mediated through cyclin D1 activation of the pRB/E2F pathway. Taken together, these results suggest that in vivo cyclin D1 overexpression can enhance tumor progression, at least in part, by potentiating the stimulatory efforts of bFGF, which is often produced by stromal cells, and the growth of adjacent tumor cells.
Tashiro
Etsu
E
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan.
Maruki
Hiroko
H
Minato
Yusuke
Y
Doki
Yuichiro
Y
Weinstein
I Bernard
IB
Imoto
Masaya
M
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D017468:Receptors, Fibroblast Growth Factor; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; D019938:Cyclin D1; C496349:Fgfr1 protein, mouse; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1