ASAP1和ARF1通过调节TAZ活动来调节rhabdomyosarcoma中的肌体差异化
Katie E Hebron1,2,3, Olivia L Perkins2,3,4, Angela Kim1
1Laboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
Molecular cancer research : MCR
|November 4, 2024
概括
ASAP1和ARF1对于拉布地肌肉肉瘤的分化至关重要. 向这些蛋白质和WWTR1 (TAZ) 可能会改善晚期狂宫肌肉瘤的分化疗法,为患者提供新的希望.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 细胞分化的过程
背景情况:
- 耐火性/复发性狂肌肉瘤 (RMS) 的预后仍然很差,尽管有积极的治疗方法.
- 差异化疗法是晚期RMS的潜在策略,因为它与肌肉前体细胞相似.
- 在临床前模型中,MEK1/2抑制 (MEKi) 是有前途的,但有效性有限.
研究的目的:
- 研究调节RAS突变PAX融合负RMS (FN-RMS) 的分化分子机制.
- 确定用于改善MEKi诱导的FN-RMS差异化的新型治疗点.
主要方法:
- 使用临床前的FN-RMS模型.
- 对ASAP1,ARF1和ARF5.5进行了淘汰研究.
- 评估了肌源性转录因子表达.
- 分析了WWTR1 (TAZ) 的酸化和活性.
- 调查了ASAP1和WWTR1双重淘汰的影响.
主要成果:
- ASAP1,ARF1和ARF5对于FN-RMS差异化是必要的.
- 丢失ASAP1或ARF1/ARF5可以抑制肌源性转录因子的表达.
- MEKi诱导了WWTR1 (TAZ) 失活,而ASAP1/ARF1损失则阻止了这种失活.
- ASAP1和WWTR1的双重淘汰挽救了MEKi诱导的差异化.
结论:
- ASAP1和ARF1是FN-RMS中MEKi诱导的肌原分化的重要调节者.
- 在ASAP1-ARF路径调节WWTR1 (TAZ) 活动,影响差异化.
- 针对YAP1/TAZ信号与ASAP1/ARF1调制结合,为FN-RMS差异化治疗提供了一个有前途的策略.
相关概念视频
mTOR Signaling and Cancer Progression
3.7K
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...
3.7K
PI3K/mTOR/AKT Signaling Pathway
3.4K
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...
3.4K
The Ras Gene
6.2K
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
Ras is a...
6.2K
Abnormal Proliferation
4.5K
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...
4.5K
MAPK Signaling Cascades
5.2K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.2K
TGF - β Signaling Pathway
7.2K
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.2K


