C-terminal sequences direct cyclin D1-CRM1 binding.
GSK-3beta-dependent phosphorylation of cyclin D1 at a conserved C-terminal residue, Thr-286, promotes CRM1-dependent cyclin D1 nuclear export. Herein, we have identified a short stretch of residues adjacent to Thr-286 that mediates CRM1 association and thus cyclin D1 nuclear export. We found that disruption of this hydrophobic patch, stretching from amino acids 290 to 295 within cyclin D1, results in constitutively nuclear cyclin D1-CDK4 complexes with an increased propensity to potentiate transformation of murine fibroblasts. Our data support a model wherein deregulation of cyclin D1 nuclear export might contribute to human neoplastic growth.
Benzeno
Sharon
S
Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Diehl
J Alan
JA
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D000939:Epitopes / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D028884:Karyopherins / Q000737:chemistry* / Q000502:physiology; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000502:physiology; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D000097606:Exportin 1 Protein
D019938:Cyclin D1; D000939:Epitopes; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D013912:Threonine; D000097606:Exportin 1 Protein