致癌Ppm1d突变使小鼠初级质瘤中的p53通路失调
Vennesa Valentine1, Abigail J Groth2, Joshua Tolliver2
1Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
bioRxiv : the preprint server for biology
|December 15, 2025
概括
突变PPM1D蛋白通过放松p53信号的调节,加速扩散中线质瘤 (DMGs) 的质生成. 这一发现表明PPM1D突变DMG可能对辐射和PARP抑制剂有反应.
科学领域:
- 神经瘤学神经瘤学
- 分子生物学分子生物学
- 癌症遗传学 癌症遗传学
背景情况:
- 扩散性中线质瘤 (DMGs) 是具有不良预后的侵袭性脑瘤.
- 大约20%的DMG在PPM1D的第6个突变中具有截断突变,导致蛋白质稳定和p53通路失调.
- 这些PPM1D突变在DMG发育和治疗反应中的确切作用仍然在很大程度上是未知的.
研究的目的:
- 调查PPM1D外基因6突变对DMG发病和进展的功能后果.
- 开发一种有条件的小鼠模型来研究突变PPM1D表达的时间和空间影响.
- 评估突变PPM1D对细胞信号通路和治疗漏洞的影响.
主要方法:
- 开发一种条件小鼠等位基因 (Ppm1d-flex-6) 来诱导截断的Ppm1d的诱导表达.
- 使用Cre-lox重组在神经干细胞和小鼠胚胎纤维细胞 (MEFs) 中建模质生成.
- 使用单细胞RNA测序来分析质瘤和MEF的转录变化.
主要成果:
- 在神经干细胞中Ppm1d-flex-6的重组加速了质生成,尽管效果不如完全失去p53.
- Ppm1d-flex-6结质瘤表现出类似于原始细胞的转录状态和上调的p53和细胞循环通路.
- 在MEF中,突变Ppm1d增强了增殖,改变了信号传递 (MAPK,PI3K-Akt),损害了DNA损伤反应,增加了对辐射和PARP抑制的敏感性.
结论:
- 在DMG中的PPM1D突变导致中间的p53通路抑制.
- 这些发现与PPM1D突变DMG的临床观察结果一致.
- PPM1D突变的DMG表现出对PARP抑制剂的放射敏感性和脆弱性,这表明了潜在的治疗策略.
更多相关视频
10:58Transposon Mediated Integration of Plasmid DNA into the Subventricular Zone of Neonatal Mice to Generate Novel Models of Glioblastoma
Published on: February 22, 2015
13.4K
09:37Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
2.1K
相关概念视频
Abnormal Proliferation
5.1K
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...
5.1K
Interactions Between Signaling Pathways
7.1K
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...
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...
7.1K
Mouse Models of Cancer Study
6.3K
Mice have long served as models for studying human biology and pathology because of their phylogenetic and physiological similarity with humans. They are also easy to maintain and breed in the laboratory, and hence, many inbred strains are now available for research. Studies on mice have contributed immeasurably to our understanding of cancer biology.
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
6.3K
The Retinoblastoma Gene
4.6K
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.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.6K
mTOR Signaling and Cancer Progression
4.6K
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...
4.6K
