Cyclin D3 expression in melanoma cells is regulated by adhesion-dependent phosphatidylinositol 3-kinase signaling and contributes to G1-S progression.
D-type cyclins regulate G1 cell cycle progression by enhancing the activities of cyclin-dependent kinases (CDKs), and their expression is frequently altered in malignant cells. We and others have previously shown that cyclin D1 is up-regulated in melanoma cells through adhesion-independent MEK-ERK1/2 signaling initiated by mutant B-RAF. Here, we describe the regulation and role of cyclin D3 in human melanoma cells. Cyclin D3 expression was enhanced in a cell panel of human melanoma cell lines compared with melanocytes and was regulated by fibronectin-mediated phosphatidylinositol 3-kinase/Akt signaling but not MEK activity. RNA interference experiments demonstrated that cyclin D3 contributed to G1-S cell cycle progression and proliferation in melanoma cells. Overexpression of cyclin D1 did not recover the effects of cyclin D3 knockdown. Finally, immunoprecipitation studies showed that CDK6 is a major binding partner for cyclin D3, whereas CDK4 preferentially associated with cyclin D1. Together, these findings demonstrate that cyclin D3 is an important regulator of melanoma G1-S cell cycle progression and that D-type cyclins are differentially regulated in melanoma cells.
Spofford
Laurie S
LS
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208, USA.
Abel
Ethan V
EV
Boisvert-Adamo
Karen
K
Aplin
Andrew E
AE
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D056743:Cyclin D3; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis*; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism*
C534696:CCND3 protein, human; D056743:Cyclin D3; D016213:Cyclins; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051361:Cyclin-Dependent Kinase 6