与死亡相关的蛋白激酶1酸化MDM2并抑制其蛋白质稳定性和功能
Mi Zhang1, Xindong Shui1, Xiaoqing Zheng1
1Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
Archives of pharmacal research
|October 7, 2023
概括
与死亡相关的蛋白激酶1 (DAPK1) 调节乳腺癌中MDM2原基因. DAPK1酸化MDM2,促进其降解,并上调瘤抑制剂p53,抑制癌症生长.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 乳腺癌是女性死亡的主要原因,通常是由复发,耐药性和转移引起的.
- 鼠标双分钟2 (MDM2) 瘤基因在乳腺癌中经常过度表达,但其调节尚未完全理解.
研究的目的:
- 确定乳腺癌中MDM2的新型调节剂.
- 阐明DAPK1在乳腺癌进展中的功能作用及其与MDM2.2的关系.
主要方法:
- 无偏见的质库选,以识别MDM2相互作用蛋白.
- 试管体内激酶测定和西式涂抹测试以评估MDM2的酸化和降解.
- 基于细胞的测试 (殖民地形成,多克索鲁比诱导的细胞死亡) 和异种移植瘤发生模型.
- 对人类乳腺癌组织中DAPK1和MDM2表达的分析.
主要成果:
- 与死亡相关的蛋白激酶1 (DAPK1) 被确定为一种新的MDM2调节剂,直接结合并化MDM2在Thr419.
- 通过DAPK1-介导的MDM2酸化通过无素-蛋白酶体通路增强了MDM2蛋白质的降解,导致p53水平增加.
- 过度表达DAPK1抑制了乳腺癌细胞的增殖,增强了多克索鲁比辛的敏感性,而DAPK1的降低则产生了相反的效果.
- 在体内,DAPK1的过度表达减少了瘤的形成,其酶活性对这种抗瘤原生效应至关重要.
- 在人类乳腺癌组织中观察到DAPK1和MDM2表达水平之间的负相关性.
结论:
- DAPK1通过酸化和促进MDM2瘤基因的降解,在乳腺癌中起到瘤抑制作用.
- 这种DAPK1-介导的途径涉及MDM2降解和p53上调,是乳腺癌治疗的潜在治疗标.
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