Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6.
D cyclins (D1, D2 and D3) and their catalytic subunits (cyclin-dependent kinases cdk4 and cdk6) have a facilitating, but nonessential, role in cell cycle entry. Tissue-specific functions for D-type cyclins and cdks have been reported; however, the biochemical properties of these kinases are indistinguishable. We report that an F box protein, Fbxo7, interacted with cellular and viral D cyclins and distinguished among the cdks that bind D-type cyclins, specifically binding cdk6, in vitro and in vivo. Fbxo7 specifically regulated D cyclin/cdk6 complexes: Fbxo7 knockdown decreased cdk6 association with cyclin and its overexpression increased D cyclin/cdk6 activity and E2F activity. Fbxo7 interacted with p27, but its enhancement of cyclin D/cdk6 activity was p21/p27 independent. Fbxo7 overexpression transformed murine fibroblasts, rendering them tumorigenic in athymic nude mice. Transformed phenotypes were dependent on cdk6, as knockdown of cdk6 reversed them. Fbxo7 was highly expressed in epithelial tumors, but not in normal tissues, suggesting that it may have a proto-oncogenic role in human cancers.
Laman
Heike
H
Cancer Research UK, Viral Oncology Group, Wolfson Institute for Biomedical Research, University College London, London, UK. hl316@cam.ac.uk
Funes
Juan M
JM
Ye
Hongtao
H
Henderson
Stephen
S
Galinanes-Garcia
Laura
L
Hara
Eiji
E
Knowles
Phillip
P
McDonald
Neil
N
Boshoff
Chris
C
D021581:Active Transport, Cell Nucleus; D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism; D056741:Cyclin D; D051361:Cyclin-Dependent Kinase 6; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D044783:F-Box Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495911:CDK6 protein, human; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases