FAK overexpression upregulates cyclin D3 and enhances cell proliferation via the PKC and PI3-kinase-Akt pathways.
We previously demonstrated that FAK-transfected HL-60 (HL-60/FAK) cells exhibit anti-apoptotic capacity. Here, we report that HL-60/FAK cells proliferate much faster than vector-transfected control (HL-60/Vect) cells with a 1.5-fold faster doubling time. This observation prompted us to investigate the mechanism of how HL-60/FAK cells augment cell proliferation. Since a protein kinase C (PKC) inhibitor, chelerythrine, or a PI3-kinase inhibitor, LY294002, suppressed cell proliferation effectively, both PKC and PI-3-kinase pathways are presumed to be involved in the cell proliferation. Among cyclins and CDKs, cyclin D3 expression was particularly prominent in the HL-60/FAK cells. Among PKC family, particularly PKCalpha, beta and eta isoforms were activated and directly associated with FAK in HL-60/FAK cells. We assumed that FAK activates PKC and PI3-kinase-Akt pathway, which resulted in marked induction of cyclin D3 expression and CDK activity.
Yamamoto
Daisuke
D
Department of Biochemistry, Kyoritsu College of Pharmacy, Shibakoen 1-5-30, Minato-ku, Tokyo 105-8512, Japan.
Sonoda
Yoshiko
Y
Hasegawa
Maki
M
Funakoshi-Tago
Megumi
M
Aizu-Yokota
Eriko
E
Kasahara
Tadashi
T
D002453:Cell Cycle; D002455:Cell Division; D056743:Cyclin D3; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis* / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D018922:HL-60 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051966:Phospholipase C gamma; D011493:Protein Kinase C / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation
D056743:Cyclin D3; D018844:Cyclin-Dependent Kinases; D016213:Cyclins; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016160:Retinoblastoma Protein; D010738:Type C Phospholipases; C534696:CCND3 protein, human; C496050:PTK2 protein, human; C494918:AKT1 protein, human