p53状态决定了自在胰腺瘤发展中的作用
Mathias T Rosenfeldt1, Jim O'Prey1, Jennifer P Morton1
1Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Nature
|December 6, 2013
概括
宏自 (自) 在癌症中起着复杂的作用. 在胰腺癌模型中,当p53存在时,阻断自会阻止瘤的进展,但当p53缺席时会加速瘤的进展.
科学领域:
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 宏自 (自) 是一种细胞降解过程,对于恒常至关重要.
- 自在癌症中的作用是复杂的,有证据表明它既有促进瘤的功能,也有抑制瘤的功能.
- 胰腺管道腺癌 (PDAC) 是一种主要的人类癌症,通常是由Kras突变驱动的.
研究的目的:
- 在基因改造的小鼠模型中研究自性在胰腺癌发展中的作用.
- 确定瘤抑制剂p53如何影响PDAC中的自的功能.
- 评估自抑制对PDAC进展的影响.
主要方法:
- 利用一个人性化的转基因小鼠模型与致癌性Kras.
- 在小鼠胰腺中遗传删除了必需的自基因 (Atg5或Atg7).
- 在未完整或缺少p53的小鼠中比较瘤进展,有和没有自基因.
- 给出了自抑制剂氧化.
主要成果:
- 自的丧失 (Atg5 / Atg7 缺乏) 在具有功能性p53.3的克拉斯突变小鼠中阻止了PDAC进展.
- 在缺乏p53的克拉斯突变小鼠中,自酶缺乏加速了瘤的发病和进展.
- 在p53缺乏的小鼠中进行的代谢分析显示,在自丧失后,葡萄糖摄取量增加和合成途径增加.
- 氧化治疗在克拉斯突变的p53缺乏的小鼠中加速了PDAC的形成.
结论:
- 自在PDAC中的作用严重依赖于p53瘤抑制剂的状态.
- 在p53缺乏的PDAC中,自作用抑制瘤生长,其抑制加速癌症.
- 这些发现对特定癌症背景下自抑制剂的治疗用途有重大影响.
相关概念视频
Abnormal Proliferation
4.0K
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...
4.0K
mTOR Signaling and Cancer Progression
3.6K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.6K
PI3K/mTOR/AKT Signaling Pathway
5.1K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
5.1K
DNA Damage can Stall the Cell Cycle
8.5K
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...
8.5K
DNA Damage Can Stall the Cell Cycle
2.4K
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...
2.4K
The Intrinsic Apoptotic Pathway
6.2K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.2K


