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優性阻害性p53変異体R248Qは口腔扁平上皮癌の運動浸潤能を増大させる [全文の要約]

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Title: 優性阻害性p53変異体R248Qは口腔扁平上皮癌の運動浸潤能を増大させる [全文の要約]
Authors: 中澤, 誠多朗 Browse this author
Keywords: gain-of-function
dominant negative mutation : DN
変異型 p53
Issue Date: 25-Mar-2014
Publisher: Hokkaido University
Abstract: 癌抑制遺伝子TP53は転写因子p53をコードしている. TP53はヒト癌の約半数で変異が認められており,その変異の多くがホットスポットと呼ばれるDNA結合領域に集中していることが知られている.これらホットスポットに変異をもったp53は通常,野生型p53結合DNA配列への結合能力を失う.さらに,このタイプの変異型p53は野生型p53の機能を喪失させる.これは優性阻害性(DN)変異とよばれ,口腔扁平上皮癌を含む様々な癌の予後リスク因子のひとつになっている.近年, DN変異型p53は単に野生型p53の機能を阻害するだけでなく,新しい機能を獲得(gain-of-function, GOF)していることがわかってきた.本研究では,まず, p53のホットスポットのひとつコドン248に生じた優性阻害性変異R248QおよびR248Wが舌癌由来細胞株SASに対して如何なるGOFを付与するのかを調べた.いずれかの変異型p53をSAS細胞に導入し,増殖能,浸潤能,運動能および接着能を観察したところ, R248Qを発現させたSAS細胞でのみ浸潤能,運動能および接着能の増強を認めた.一方,いずれの変異型p53を発現させても, SAS細胞の増殖能には変化がみられなかった.次に内在性にR248Qを発現している舌癌由来細胞株HSC4および内在性にR248Wを発現している下顎歯肉癌由来細胞株Ca9-22の変異型p53の発現をRNA干渉法によって抑制し,同様の実験を行った.その結果, p53の発現抑制によってHSC4細胞の浸潤能,運動能および接着能は低下するが, Ca9-22細胞のそれらは変化しないことがわかった.以上の結果より, R248Q変異型p53はヒト口腔癌細胞において高い運動・浸潤能の獲得に働くことが示された.
The tumor suppressor gene TP53(gene) codes for a transcription factor which transactivates its target genes responsible for cell cycle arrest, DNA repair, apoptosis, and senescence. TP53(gene) is well known to be the most frequent target of genetic mutations in nearly half of human cancers including oral squamous cell carcinoma (OSCC). Many p53 mutants including R248Q and R248W, not only lose its tumor-suppressor activities, but also interfere with the functions of wild-type p53; this is so-called dominant-negative (DN) mutation. The DN p53 mutation is a predictor of poor outcome in patients with various cancers, and also a risk factor for metastatic recurrence in patients with oral squamous cell carcinomas. Recently it has been reported that DN p53 mutants acquire new oncogenic activities, which is named gain-of-function(GOF). This study aimed at determining whether R248Q and R248W were involved in OSCC cells’ acquiring aggressive phenotypes, using SAS, HSC4 and Ca9-22 cell lines. First, two mutants p53, R248Q and R248W, were respectively transfected into SAS cells harboring recessive-type p53 (E336X). As a result, SAS cells expressing R248Q showed highly spreading, motile and invasive activities compared to parent or mock-transfected cells whereas those expressing R248W did not increase those activities; and cell growth activities of the two transfectants were both similar to that of parent or of mock-transfected cells. Secondly, in HSC4 cells harboring R248Q and Ca9-22 cells harboring R248W, expressions of the mutants p53 were inhibited by the transfection with siRNAs targeting p53. The inhibition of the mutants p53 decreased spreading, motile and invasive activities of HSC4 cells whereas it did not affect those activities of Ca9-22 cells. These findings suggest that R248Q p53 mutation, but not R248W p53 mutantion, induces more motile and invasive potentials in human OSCC cells.
Description: この博士論文全文の閲覧方法については、以下のサイトをご参照ください。
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Conffering University: 北海道大学
Degree Report Number: 甲第11258号
Degree Level: 博士
Degree Discipline: 歯学
Examination Committee Members: (主査) 教授 山崎 裕, 教授 進藤 正信, 教授 鄭 漢忠, 准教授 浜田 淳一 (遺伝子病制御研究所)
Degree Affiliation: 歯学研究科(口腔医学専攻)
Type: theses (doctoral - abstract of entire text)
Appears in Collections:学位論文 (Theses) > 博士 (歯学)
課程博士 (Doctorate by way of Advanced Course) > 歯学院(Graduate School of Dental Medicine)

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