Transitory FGF treatment results in the long-lasting suppression of the proliferative response to repeated FGF stimulation.
Transitory FGF treatment results in the long-lasting suppression of the proliferative response to repeated FGF stimulation.
复制标题
短暂的 FGF 治疗会导致对重复 FGF 刺激的增殖反应的长期抑制。
DOI：
10.1002/jcb.24731
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发表时间：
2014
影响因子：
4
通讯作者：
Prudovsky,Igor
中科院分区：
文献类型：
--
作者：
Poole,Ashleigh;Knowland,Nicholas;Cooper,Emily;Cole,Rebecca;Wang,Hongchuan;Booth,Lucas;Kacer,Doreen;Tarantini,Francesca;Friesel,Robert;Prudovsky,Igor
FGF作为单一生长因子应用于静止小鼠成纤维细胞诱导一轮DNA复制，但持续刺激导致下一个细胞周期的G1期停止。我们假设FGF刺激诱导了细胞记忆的建立，这阻止了重复或连续使用FGF的增殖反应。当在一次和重复FGF处理之间引入2-5天的静息期时，成纤维细胞对二次FGF应用的反应不能有效地复制。在第一次FGF刺激过程中，“FGF记忆”的建立不需要DNA合成，而是依赖于FGF受体的活性、MEK、p38 MAPK和NFκB信号传导以及蛋白质合成。虽然二次刺激导致复制率大幅下降，但我们没有观察到形态学变化、Erk1/2磷酸化和cyclin D1诱导的任何衰减。然而，二次FGF刺激未能诱导细胞周期蛋白A的表达，而细胞周期蛋白A是细胞从G1期向S期发展的关键。在原发性FGF刺激期间，用广谱组蛋白去乙酰化酶抑制剂处理细胞，恢复了对继发性FGF治疗的增殖反应，这表明“FGF记忆”的建立可能基于表观遗传变化。我们认为“FGF记忆”可以防止细胞损伤和炎症的增生性反应，这与FGF的产生和分泌增强有关。“FGF记忆”可能是重组FGF有效应用于溃疡、缺血和伤口治疗的天然障碍。j .细胞。中国生物医学工程学报，2014,31(2):387 - 388。©2013 Wiley期刊公司
FGF applied as a single growth factor to quiescent mouse fibroblasts induces a round of DNA replication, however continuous stimulation results in arrest in the G1 phase of the next cell cycle. We hypothesized that FGF stimulation induces the establishment of cell memory, which prevents the proliferative response to repeated or continuous FGF application. When a 2–5 days quiescence period was introduced between primary and repeated FGF treatments, fibroblasts failed to efficiently replicate in response to secondary FGF application. The establishment of “FGF memory” during the first FGF stimulation did not require DNA synthesis, but was dependent on the activity of FGF receptors, MEK, p38 MAPK and NFκB signaling, and protein synthesis. While secondary stimulation resulted in strongly decreased replication rate, we did not observe any attenuation of morphological changes, Erk1/2 phosphorylation and cyclin D1 induction. However, secondary FGF stimulation failed to induce the expression of cyclin A, which is critical for the progression from G1 to S phase. Treatment of cells with a broad range histone deacetylase inhibitor during the primary FGF stimulation rescued the proliferative response to the secondary FGF treatment suggesting that the establishment of “FGF memory” may be based on epigenetic changes. We suggest that “FGF memory” can prevent the hyperplastic response to cell damage and inflammation, which are associated with an enhanced FGF production and secretion. “FGF memory” may present a natural obstacle to the efficient application of recombinant FGFs for the treatment of ulcers, ischemias, and wounds. J. Cell. Biochem. 115: 874–888, 2014. © 2013 Wiley Periodicals, Inc.