Constitutive RelA activation mediated by Nkx3.2 controls chondrocyte viability
Constitutive RelA activation mediated by Nkx3.2 controls chondrocyte viability
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DOI：
10.1038/ncb1538
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发表时间：
2007-03-01
影响因子：
21.3
通讯作者：
Kim, Dae-Won
中科院分区：
文献类型：
--
作者：
Park, Minsun;Yong, Yeryoung;Kim, Dae-Won
在软骨内骨化过程中，一个占脊椎动物骨形成的大部分的过程，与增殖的软骨细胞相比，肥大的软骨细胞显示出更大的凋亡敏感性。然而，这种现象背后的分子机制仍不清楚。Nkx3.2是NK类同源异型蛋白的成员，最初在软骨形成前体细胞中表达，后来在软骨成熟期间，其表达限于增殖的软骨细胞。在这里，我们表明，核因子κ B（NF-κ B）途径是软骨细胞活力所必需的，Nkx3.2通过组成性激活RelA支持软骨细胞存活。虽然信号依赖性NF-κ B活化已被深入研究，但配体非依赖性NF-κ B活化知之甚少。本文提供的数据支持NF-κ B激活的一种新的配体非依赖性机制，即Nkx 3.2通过直接的蛋白质-蛋白质相互作用将ReIA-I κ B α异聚体复合物募集到细胞核中，并通过细胞核中蛋白酶体依赖性I κ B α降解激活RelA。此外，我们证明，阶段特异性NF-κ B激活，Nkx3.2介导的，调节软骨细胞的活力在软骨成熟。
During endochondral ossification, a process that accounts for the majority of bone formation in vertebrates, hypertrophic chondrocytes display a greater susceptibility to apoptosis when compared to proliferating chondrocytes. However, the molecular mechanisms underlying this phenomenon remain unclear. Nkx3.2, a member of the NK class of homeoproteins, is initially expressed in chondrogenic precursor cells, and later, during cartilage maturation, its expression is restricted to proliferating chondrocytes. Here, we show that the nuclear factor kappa B (NF-kappa B) pathway is required for chondrocyte viability and that Nkx3.2 supports chondrocyte survival by constitutively activating RelA. Although signal-dependent NF-kappa B activation has been intensively studied, ligand-independent NF-kappa B activation is poorly understood. The data presented here support a novel ligand-independent mechanism of NF-kappa B activation, whereby Nkx3.2 recruits the ReIA-I kappa B alpha heteromeric complex into the nucleus by direct protein-protein interactions and activates RelA through proteasome-dependent I kappa B alpha degradation in the nucleus. Furthermore, we demonstrate that stage-specific NF-kappa B activation, mediated by Nkx3.2, regulates chondrocyte viability during cartilage maturation.