title: Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer.
abstract: Cyclin D1 is an important regulator of cell cycle progression. Phosphorylation of cyclin D1 at Thr286 by GSK3β triggers its nuclear export and cytoplasmic proteolysis via the 26S proteasome. Cyclin D1 overexpression is a common event in various types of human cancers; however, reports of mutations are extremely rare. We analyzed mutations of the cyclin D1 gene, CCND1, in 88 endometrial cancer tissue specimens and detected mutations in 2 cases (2.3%). Both were unreported mutations with substitution of threonine to isoleucine at codon 286 (T286I). These two tumors harbored coexisting mutations in K-ras, PIK3CA and/or PTEN and showed accumulation of cyclin D1 in the nucleus by immunohistochemistry. Furthermore, we analyzed the functions of mutant cyclin D1 (T286I) by luciferase assays, immunofluorescence, western blotting and clonogenic cell survival assays in HEK-293T cells. We found that exogenous mutant cyclin D1 (T286I) accumulated in the nuclei in HEK-293T cells, and that it inhibited the expression of pRb. Additionally, the number of colonies was increased by introduction of mutant cyclin D1 (T286I) compared to that of wild-type cyclin D1. In conclusion, we identified an unreported CCND1 mutation (T286I) in two endometrial cancers and revealed that the mutation was functional for inducing cell proliferation in human cells.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Oda
authors.forename: Osamu
authors.initials: O
authors.lastname: Hiraike-Wada
authors.forename: Takahiro
authors.initials: T
authors.lastname: Koso
authors.forename: Aki
authors.initials: A
authors.lastname: Miyasaka
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kashiyama
authors.forename: Michihiro
authors.initials: M
authors.lastname: Tanikawa
authors.forename: Kenbun
authors.initials: K
authors.lastname: Sone
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nagasaka
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Osamu
authors.initials: O
authors.lastname: Tetsu
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.forename: Shiro
authors.initials: S
authors.lastname: Kozuma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D019938:Cyclin D1 / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D011905:Genes, ras; D057809:HEK293 Cells; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C530104:CCND1 protein, human; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins