A critical role for FBXW8 and MAPK in cyclin D1 degradation and cancer cell proliferation.
Cyclin D1 regulates G1 progression. Its transcriptional regulation is well understood. However, the mechanism underlying cyclin D1 ubiquitination and its subsequent degradation is not yet clear. We report that cyclin D1 undergoes increased degradation in the cytoplasm during S phase in a variety of cancer cells. This is mediated by phosphorylation at Thr286 through the activity of the Ras/Raf/MEK/ERK cascade and the F-box protein FBXW8, which is an E3 ligase. The majority of FBXW8 is expressed in the cytoplasm during G1 and S phase. In contrast, cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm in S phase. Increased cyclin D1 degradation is linked to association with FBXW8 in the cytoplasm, and enhanced phosphorylation of cyclin D1 through sustained ERK1/2 signaling. Depletion of FBXW8 caused a significant accumulation of cyclin D1, as well as sequestration of CDK1 in the cytoplasm. This resulted in a severe reduction of cell proliferation. These effects could be rescued by constitutive nuclear expression of cyclin D1-T286A. Thus, FBXW8 plays an essential role in cancer cell proliferation through proteolysis of cyclin D1. It may present new opportunities to develop therapies targeting destruction of cyclin D1 or its regulator E3 ligase selectively.
Okabe
Hiroshi
H
Department of Pathology, School of Medicine, University of California San Francisco, San Francisco, California, United States of America; UCSF Comprehensive Cancer Center, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Lee
Sang-Hyun
SH
Phuchareon
Janyaporn
J
Albertson
Donna G
DG
McCormick
Frank
F
Tetsu
Osamu
O
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D051379:Mice; D046912:Multiprotein Complexes; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000737:chemistry; D025801:Ubiquitin / Q000378:metabolism
C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; D044783:F-Box Proteins; C526069:FBXW8 protein, human; C513332:Fbxw8 protein, mouse; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D019938:Cyclin D1; D013912:Threonine; D046988:Proteasome Endopeptidase Complex