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Activated stress response pathways within multicellular aggregates utilize an autocrine component

机译:多细胞聚集体中的活化应激反应途径利用自分泌成分

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Multicellular aggregates (spheroids) of primary human foreskin fibroblasts (HFF-2) and a glioblastoma cell line (T98G) entered and exited from long term (2 weeks) metabolic arrest utilizing an autocrine response. Cytokine production (specifically IFN-gamma) activated a Gadd45 alpha/p3g pathway that led to increased AP-1 (c-jun and ATF3) transcription factor levels, augmenting cytokine production in an autocrine fashion. Whereas HFF-2 aggregates were capable of surviving long term arrest and recovery during NF-kappa B inhibition independent of JNK activation, T98G aggregates were not. Such endogenous processes are not easily observed with adherent monolayer cell culturing systems, strongly suggesting that more emphasis needs to be placed on determining the operational signal transduction cascades within multicellular aggregates. Extracellular inputs such as spheroid formation, arrest, and regrowth as monolayers invoke intracellular signaling responses converging at the AP-1 transcription factor level. Variations in responses are both cell type and transformation state dependent and require an autocrine cytokine component. The data are discussed in relation to the wounding response and avascular tumor growth mechanisms. (c) 2006 Elsevier Inc. All rights reserved.
机译:主要人类包皮成纤维细胞(HFF-2)和胶质母细胞瘤细胞系(T98G)的多细胞聚集体(球体)利用自分泌反应进入和退出长期(2周)代谢停滞。细胞因子的产生(特别是IFN-γ)激活了Gadd45 alpha / p3g途径,从而导致AP-1(c-jun和ATF3)转录因子水平增加,以自分泌方式增加了细胞因子的产生。尽管HFF-2聚集体能够独立于JNK活化而在NF-κB抑制期间长期停滞和恢复,但T98G聚集体却不能。用贴壁单层细胞培养系统不容易观察到这种内源性过程,强烈暗示着需要更加重视确定多细胞聚集体中的操作性信号转导级联反应。细胞外输入(例如球体形成,停滞和单层再生长)会调用在AP-1转录因子水平收敛的细胞内信号反应。反应的变化取决于细胞类型和转化状态,并且需要自分泌细胞因子成分。讨论了有关伤口反应和无血管肿瘤生长机制的数据。 (c)2006 Elsevier Inc.保留所有权利。

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