p53シグナル伝達におけるUSP28細胞機能の薬理学的尋問

Ariana S Bratt¹, Susan Kilgas², Maria I Tarazona Guzman¹

¹Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Cell chemical biology

|September 3, 2025

まとめ

研究者は,USP28 (デウビキチン化酵素) の特定の阻害剤であるCAS-010を開発し,p53シグナル伝達と細胞運命を研究した. この化学探知器はユビキチン信号伝達経路を理解するのに役立ちます

科学分野:

生物化学
分子生物学
化学生物学

背景:

デウビキチン化酵素 (DUB) は,タンパク質の分解を含む重要な細胞プロセスを調節する.
DUBの機能の理解は,特定の化学探査機の欠如によって妨げられています.
USP28は様々な細胞経路に関与するDUBですが,その正確な役割についてはさらなる調査が必要です.

研究の目的:

USP28のための特定の化学探査機を開発し,検証する.
p53のトランザクティベーションと53BP1- USP28の相互作用におけるUSP28の役割を調査する.
細胞サイクル制御と細胞運命を研究するためのツールを提供する.

主な方法:

ユビキチンと競合するUSP28阻害剤CAS-010の開発.
構造に基づく薬剤設計とSAR分析による抑制剤の選択性
阻害剤の効能と選択性を決定する生化学的測定
細胞ベースの測定は,p53のトランザクティベーションに対する標的効果を検証する.
53BP1-USP28の相互作用に対するCAS-010の影響を調査する.

主要な成果:

CAS-010は,USP28の低ナノモラー,選択的阻害剤であり,USP25に対して何らかの活性がある.
結晶構造は阻害剤の選択性とSARの傾向を合理化しました.
CAS-010によるp53トランザクティベーションの有効な標的抑制
CAS-010が53BP1-USP28の相互作用を妨害し,USP28の触媒的役割を強調することが示されました.
陰性対照群 (WPT-086) と阻害剤耐性突然変異体が開発され,さらなる研究が行われる.

結論:

CAS-010は,USP28を研究するための有効な化学ツールです.
USP28の触媒作用は53BP1とUSP28の相互作用に不可欠である.
これらのツールは,p53媒介の細胞サイクル制御と細胞運命を決定するUSP28の役割に関する研究を進めます.

キーワード:

53BP1 について DUB について USP28 オーケストラ化学探査機クリスタル構造デウビキチン化酵素 p53 について p53 転写制御

さらに関連する動画

10:55

Purification of Ubiquitinated p53 Proteins from Mammalian Cells

Published on: March 21, 2022

2.3K

09:32

Procedure and Key Optimization Strategies for an Automated Capillary Electrophoretic-based Immunoassay Method

Published on: September 10, 2017

11.1K

関連する概念動画

02:23

Abnormal Proliferation

4.6K

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...

4.6K

02:37

DNA Damage can Stall the Cell Cycle

9.3K

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...

9.3K

01:23

Negative Regulator Molecules

35.9K

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.

35.9K

01:19

Interactions Between Signaling Pathways

6.4K

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...

6.4K

02:04

Covalently Linked Protein Regulators

7.1K

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....

7.1K

02:34

Inhibition of Cdk Activity

4.9K

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...