The roles of versican V1 and V2 isoforms in cell proliferation and apoptosis.
Versican is a large chondroitin sulfate proteoglycan belonging to the lectican family. Alternative splicing of versican generates at least four isoforms named V0, V1, V2, and V3. We have shown that the versican V1 isoform not only enhanced cell proliferation, but also modulated cell cycle progression and protected the cells from apoptosis. Futhermore, the V1 isoform was able to not only activate proto-oncogene EGFR expression and modulate its downstream signaling pathway, but also induce p27 degradation and enhance CDK2 kinase activity. As well, the V1 isoform down-regulated the expression of the proapoptotic protein Bad. By contrast, the V2 isoform exhibited opposite biological activities by inhibiting cell proliferation and down-regulated the expression of EGFR and cyclin A. Furthermore, V2 did not contribute apoptotic resistance to the cells. In light of these results, we are reporting opposite functions for the two versican isoforms whose expression is differentially regulated. Our studies suggest that the roles of these two isoforms are associated with the subdomains CSbeta and CSalpha, respectively. These results were confirmed by silencing the expression of versican V1 with small interfering RNA (siRNA), which abolished V1-enhanced cell proliferation and V1-induced reduction of apoptosis.
Sheng
Wang
W
Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
Wang
Guizhi
G
Wang
Yelina
Y
Liang
Jiyong
J
Wen
Jianping
J
Zheng
Peng-Sheng
PS
Wu
Yaojiong
Y
Lee
Vivian
V
Slingerland
Joyce
J
Dumont
Dan
D
Yang
Burton B
BB
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry* / Q000502:physiology*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D019927:Cyclin E; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006820:Hyaluronic Acid / Q000737:chemistry; D047468:Immunoprecipitation; D037181:Lectins, C-Type; D051379:Mice; D008957:Models, Genetic; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000737:chemistry; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry; D010766:Phosphorylation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry; D053675:Versicans
C475820:CCNE1 protein, human; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D016895:Culture Media, Serum-Free; D019927:Cyclin E; D017931:DNA Primers; D037181:Lectins, C-Type; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C508322:VCAN protein, human; C508323:Vcan protein, mouse; D053675:Versicans; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006820:Hyaluronic Acid; D066246:ErbB Receptors; D010744:Phosphoric Monoester Hydrolases