title: Selective usage of D-Type cyclins by Ewing's tumors and rhabdomyosarcomas.
abstract: The genetic mechanisms that control proliferation of childhood musculoskeletal malignancies, notably Ewing's tumor (ET) and rhabdomyosarcoma (RMS), remain largely unknown. Most human cancers appear to overexpress at least one of the G1 cyclins (cyclins D1, D2, D3, E1, and E2) to bypass normal regulation of cell cycle G1 progression. We compared the gene expression profiles of 7 ET and 13 RMS primary tumor samples and found overexpression of cyclin D1 in all 7 ET samples. In contrast, RMS samples expressed higher levels of cyclin D2, cyclin D3, and cyclin E1. This was confirmed by quantitative reverse transcription-polymerase chain reaction and Western blot. The relative roles of RAS-extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3'-kinase (PI3K)-AKT pathways in the regulation of D-type cyclin expression in these tumors were then assessed. Inhibition of either pathway reduced expression of cyclins D1, D2, and D3 in RMS lines, whereas only PI3K inhibitors blocked cyclin D1, D2, and D3 expression in ET lines. Furthermore, PI3K-AKT appeared to regulate D-type cyclin transcription in RMS lines through FKHR and FKHRL1. Finally, the role of the ET-associated EWS-FLI1 fusion gene in regulating D cyclin expression was studied. Inhibition of EWS-FLI1 expression in the TC71 ET line decreased cyclin D1 levels but increased cyclin D3 levels. In contrast, induction of EWS-FLI1 expression in the RD RMS cell line increased cyclin D1 expression but decreased cyclin D3 expression. Our results demonstrate distinct regulation of D-type cyclins in ET and RMS and indicate that EWS-FLI1 can modulate the expression of D-type cyclins independent of cellular backgrounds.
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Zhang
authors.forename: Siwen
authors.initials: S
authors.lastname: Hu
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Schofield
authors.forename: Poul H B
authors.initials: PH
authors.lastname: Sorensen
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Triche
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034802:RNA-Binding Protein EWS; D012208:Rhabdomyosarcoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors; C475820:CCNE1 protein, human; C106031:EWS-FLI fusion protein; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C494918:AKT1 protein, human