Mutations in Fbx4 inhibit dimerization of the SCF(Fbx4) ligase and contribute to cyclin D1 overexpression in human cancer.
SCF(Fbx4) was recently identified as the E3 ligase for cyclin D1. We now describe cell-cycle-dependent phosphorylation and dimerization of Fbx4 that is regulated by GSK3beta and is defective in human cancer. We present data demonstrating that a pathway involving Ras-Akt-GSK3beta controls the temporal phosphorylation and dimerization of the SCF(Fbx4) E3 ligase. Inhibition of Fbx4 activity results in accumulation of nuclear cyclin D1 and oncogenic transformation. The importance of this regulatory pathway for normal cell growth is emphasized by the prevalence of mutations in Fbx4 in human cancer that impair dimerization. Collectively, these data reveal that inactivation of the cyclin D1 E3 ligase likely contributes to cyclin D1 overexpression in a significant fraction of human cancer.
Barbash
Olena
O
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Zamfirova
Petia
P
Lin
Douglas I
DI
Chen
Xiangmei
X
Yang
Ke
K
Nakagawa
Hiroshi
H
Lu
Fengmin
F
Rustgi
Anil K
AK
Diehl
J Alan
JA
D000818:Animals; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D012694:Serine; D014162:Transfection; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
D056741:Cyclin D; D016213:Cyclins; D044783:F-Box Proteins; C508146:FBXO4 protein, human; D012694:Serine; D044843:SKP Cullin F-Box Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D018631:ras Proteins