Connexin43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27.
Many lines of evidence indicate that connexin genes expressing gap junction (GJ) proteins inhibit tumor cell proliferation. However, the precise molecular mechanisms remain unclear. In this study, we show that overexpression of connexin43 (Cx43) suppressed proliferation of human osteosarcoma U2OS cells through inhibition of the cell cycle transition from G1 to S phase. This inhibition was attributed to a significant accumulation of the hypophosphorylated retinoblastoma (Rb) protein, which was causally related to decreases in the kinase activities of cyclin-dependent kinases (CDKs) 2 and 4. Enforced Cx43 expression markedly increased the level of the CDK inhibitor p27. This increase resulted from an increased synthesis and a reduced degradation of the p27 proteins, but not influence of the p27 mRNA. Moreover, we show that the Cx43-modulated GJ function was the main contributor to the elevation in p27 levels, in which cAMP was involved. These data suggest that Cx43 appears to inhibit proliferation of U2OS cells by increasing the levels of p27 proteins via post-transcriptional regulatory mechanisms.
Zhang
Y W
YW
Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, 113-8549 Tokyo Japan.
Morita
I
I
Ikeda
M
M
Ma
K W
KW
Murota
S
S
D001483:Base Sequence; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D042846:CDC2-CDC28 Kinases; D002450:Cell Communication / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D018031:Connexin 43 / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D017931:DNA Primers; D017629:Gap Junctions / Q000502:physiology; D006801:Humans; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012323:RNA Processing, Post-Transcriptional; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018031:Connexin 43; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases