Fbxw7/Cdc4は,p53依存型,ハプロイン不十分な腫瘍抑制遺伝子である

Jian-Hua Mao¹, Jesus Perez-Losada, Di Wu

¹Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, California 94143, USA.

Nature

|December 14, 2004

まとめ

Fbxw7遺伝子は腫瘍抑制剤として作用し,その喪失は,特にp53欠乏したマウスのがん発症に寄与する. このハプロイン不十分な腫瘍抑制遺伝子は,

科学分野:

腫瘍学腫瘍学
分子生物学は分子生物学である.
遺伝学遺伝学とは

背景:

FBXW7/hCDC4遺伝子は,染色体の安定性にとって重要なユビキチンリガスをコードする.
腫瘍生成は,遺伝子変異と腫瘍抑制遺伝子の喪失を含む複雑なプロセスです.
p53経路は,DNA損傷への反応として,細胞サイクル停止とアポトーシスの重要な調節器である.

研究の目的:

哺乳類の遺伝子スクリーンを用いて,腫瘍形成に関与するp53依存性腫瘍抑制遺伝子を特定する.
マウスのFbxw7遺伝子のがん発症における役割とそのp53.3との関係を調査する.
Fbxw7の喪失が遺伝的不安定性と腫瘍形成に寄与する分子メカニズムを理解する.

主な方法:

放射線誘発性リンパ腫におけるp53依存遺伝子の検出のための哺乳類遺伝子スクリーニング.
p53+/-およびp53-/-マウスにおけるFbxw7遺伝子のヘテロジゴシティの喪失と変異率の分析.
Fbxw7+/-マウスとp53欠乏マウスにおける腫瘍スペクトル分析.
Fbxw7欠乏したマウス胚線維芽細胞とFbxw7ノックダウンした野生型の細胞におけるタンパク質レベル (オーロラ-Aキナーゼ,c-Jun,Notch4,サイクリンE) の分析.

主要な成果:

マウスFbxw7遺伝子は,p53-依存性腫瘍抑制剤として特定されました.
ヘテロジゴシティの頻繁な喪失とFbxw7の変異は,p53+/-マウスからの放射線誘発リンパ腫で観察されました.
Fbxw7ハプロイン欠乏症は,放射線による腫瘍発生に対する感受性を高めます.
p53欠乏したマウスのFbxw7の喪失は,より広範な表皮腫瘍 (肺,肝臓,卵巣) を引き起こした.
Fbxw7欠乏症は,オーロラ-Aキナーゼ,c-Jun,Notch4のレベルが上昇した結果でした.

結論:

Fbxw7は,p53に依存した方法で,ハプロイン不十分な腫瘍抑制遺伝子として機能する.
Fbxw7の喪失は,遺伝子の不安定化に寄与し,おそらくAurora-Aキナーゼの活性化によるものです.
これらの発見は,ヒトがんにおけるFbxw7変異の早期発生の論理的根拠を提供します.

さらに関連する動画

10:04

Establishment of Proliferative Tetraploid Cells from Nontransformed Human Fibroblasts

Published on: January 8, 2017

14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

関連する概念動画

01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.

02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...

02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...

02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...

01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...

02:36

DNA Damage Can Stall the Cell Cycle

関連する実験動画