FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence.
FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence.
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DOI：
10.1016/j.bone.2010.03.021
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发表时间：
2010-07
期刊：
影响因子：
4.1
通讯作者：
Wilcox, William R.
中科院分区：
文献类型：
--
作者：
Krejci, Pavel;Prochazkova, Jirina;Smutny, Jiri;Chlebova, Katarina;Lin, Patricia;Aklian, Anie;Bryja, Vitezslav;Kozubik, Alois;Wilcox, William R.
RAS-ERK MAP激酶信号传导途径的致癌激活可导致不受控制的增殖，但也可导致细胞凋亡或过早细胞衰老，两者都被认为是细胞永生化和转化的天然保护屏障。在FGFR 3相关的骨骼发育不良中，FGFR 3受体酪氨酸激酶的致癌突变引起软骨生长的严重抑制，导致严重侏儒症，尽管FGFR 3作用的许多精确机制仍不清楚。突变的FGFR 3诱导软骨细胞中ERK途径的组成性激活，并且显著地，还可以根据胎龄在生长的软骨中引起增加的增殖和凋亡。在此，我们证明FGFR 3信号传导也能够诱导软骨细胞的过早衰老，表现为可逆的ERK依赖性生长停滞，伴随细胞形状改变、细胞外基质损失、衰老标志物（α-葡萄糖苷酶、纤维连接蛋白、小窝蛋白1、层粘连蛋白A、SM 22 α和TIMP 1）上调以及衰老相关β-半乳糖苷酶活性诱导。我们的数据支持一种模型，即FGFR 3信号通过利用最初设计用于消除携带活化癌基因的细胞的细胞反应来抑制软骨生长。
Oncogenic activation of the RAS-ERK MAP kinase signaling pathway can lead to uncontrolled proliferation but can also result in apoptosis or premature cellular senescence, both regarded as natural protective barriers to cell immortalization and transformation. In FGFR3-related skeletal dyplasias, oncogenic mutations in the FGFR3 receptor tyrosine kinase cause profound inhibition of cartilage growth resulting in severe dwarfism, although many of the precise mechanisms of FGFR3 action remain unclear. Mutated FGFR3 induces constitutive activation of the ERK pathway in chondrocytes and, remarkably, can also cause both increased proliferation and apoptosis in growing cartilage, depending on the gestational age. Here, we demonstrate that FGFR3 signaling is also capable of inducing premature senescence in chondrocytes, manifested as reversible, ERK-dependent growth arrest accompanied by alteration of cellular shape, loss of the extracellular matrix, upregulation of senescence markers (α-GLUCOSIDASE, FIBRONECTIN, CAVEOLIN 1, LAMIN A, SM22α and TIMP 1), and induction of senescence-associated β-GALACTOSIDASE activity. Our data support a model whereby FGFR3 signaling inhibits cartilage growth via exploiting cellular responses originally designed to eliminate cells harbouring activated oncogenes.
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影响因子：
20.3
作者：
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通讯作者：
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影响因子：
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通讯作者：
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