The FBXW7 beta-form is suppressed in human glioma cells.
FBXW7 (F-box and WD40 domain protein 7) is an F-box protein with 7 tandem WDs (tryptophan-aspartic acid) that functions as a phosphoepitope-specific substrate recognition component of SCF (Skp1-Cul1-F-box protein) ubiquitin ligases and catalyzes the ubiquitination of proteins promoting cell proliferation, such as CCNE1, MYC, AURKA, NOTCH1, and JUN, which are frequently activated in a wide range of human cancers. FBXW7 is a candidate tumor suppressor, and mutations have been reported in some human tumors. In this study, we analyzed 84 human tumor cell lines in search for genetic alterations of FBXW7, as well as mRNA and protein expressional changes, and compared them with expression levels of the CCNE1, MYC, and AURKA proteins. We found a novel nonsense mutation in a colon cancer cell line SCC and confirmed the missense mutations in SKOV3, an ovarian cancer cell line, and LoVo, a colon cancer cell line. Moreover, suppressed expression of FBXW7 accompanied by activation of the target proteins were observed in ovarian, colon, endometrial, gastric, and prostate cancers. It is notable that highly suppressed mRNA expression of the FBXW7 beta-form was found in all the human glioma cell lines analyzed; enhanced expressions of CCNE1, MYC, and AURKA were observed in these cells. Our present results imply that FBXW7 plays a pivotal role in many tissues by controlling the amount of cell cycle promoter proteins and that dysfunction of this protein is one of the essential steps in carcinogenesis in multiple organs.
Gu
Zhaodi
Z
Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-Machi, Sendai, Japan.
Inomata
Kenichi
K
Ishizawa
Kota
K
Horii
Akira
A
D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D003110:Colonic Neoplasms / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D015513:Oncogene Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
C475820:CCNE1 protein, human; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D015513:Oncogene Proteins; D020033:Protein Isoforms; D044767:Ubiquitin-Protein Ligases