TM4SF5 accelerates G1/S phase progression via cytosolic p27Kip1 expression and RhoA activity.
Transmembrane 4 L six family member 5 (TM4SF5) causes epithelial-mesenchymal transition (EMT) for aberrant cell proliferation. However, the effects of TM4SF5 expression on cell cycle are unknown so far. In this study, using hepatocytes that either ectopically or endogenously express TM4SF5 and human hepatocarcinoma tissues, the role of TM4SF5 in G1/S phase progression was examined. We found that TM4SF5 expression accelerated G1/S phase progression with facilitated cyclin D1 and E expression and Rb phosphorylation. Furthermore, TM4SF5 enhanced trafficking of CDK4 and cyclin D1 into the nucleus and induced complex formation between them. However, TM4SF5-facilitated G1/S phase progression was blocked by silencing of p27Kip1 using siRNA or by infection of active RhoA. Pharmacological inhibition of ROCK accelerated the G1/S phase progression of control TM4SF5-unexpressing cells. Altogether, these observations suggest that TM4SF5 accelerates G1/S phase progression with facilitated CDK4/cyclin D1 entry into the nucleus, which might be supported by TM4SF5-mediated actin reorganization through cytosolic p27Kip1 expression and Rho GTPase activity.
Kim
Hyeonjung
H
Department of Tumor Biology, Cancer Research Institute, Cell Dynamics Research Center, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
Kang
Minkyung
M
Lee
Sin-Ae
SA
Kwak
Tae Kyoung
TK
Jung
Oisun
O
Lee
Hyo Jeong
HJ
Kim
Sung-Hoon
SH
Lee
Jung Weon
JW
D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D034741:RNA, Small Interfering; C111029:TM4SF5 protein, human; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054460:rho-Associated Kinases; D051358:Cyclin-Dependent Kinase 4; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein