ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology: Implication for Coffin-Lowry syndrome
ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology: Implication for Coffin-Lowry syndrome
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DOI：
10.1016/s0092-8674(04)00344-7
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发表时间：
2004-04-30
期刊：
影响因子：
64.5
通讯作者：
Karsenty, G
中科院分区：
文献类型：
--
作者：
Yang, XG;Matsuda, K;Karsenty, G
棺材-Lowry综合征(CLS)是一种与骨骼异常相关的X连锁精神发育迟滞疾病。该基因在CLS中突变，名为RSK2，编码一种生长因子调节的激酶。然而，与CLS相关的骨骼异常的细胞和分子基础仍不清楚。在这里，我们证明RSK2是成骨细胞分化和功能所必需的。我们确定转录因子ATF4是RSK2的关键底物，对于成骨细胞分化的及时启动、成骨细胞的终末分化和成骨细胞特异性基因的表达都是必需的。此外，RSK2和ATF4在转录后调节I型胶原的合成，I型胶原是骨基质的主要成分。因此，ATF4缺乏会导致胚胎发育期间骨形成延迟，并导致出生后整个生命周期的骨量减少。这些发现证实ATF4是成骨细胞分化和功能的关键调节因子，并提示RSK2缺乏ATF4的磷酸化可能与CLS的骨骼表型有关。
Coffin-Lowry Syndrome (CLS) is an X-linked mental retardation condition associated with skeletal abnormalities. The gene mutated in CLS, RSK2, encodes a growth factor-regulated kinase. However, the cellular and molecular bases of the skeletal abnormalities associated with CLS remain unknown. Here, we show that RSK2 is required for osteoblast differentiation and function. We identify the transcription factor ATF4 as a critical substrate of RSK2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression. Additionally, RSK2 and ATF4 posttranscriptionally regulate the synthesis of Type I collagen, the main constituent of the bone matrix. Accordingly, Atf4-deficiency results in delayed bone formation during embryonic development and low bone mass throughout postnatal life. These findings identify ATF4 as a critical regulator of osteoblast differentiation and function, and indicate that lack of ATF4 phosphorylation by RSK2 may contribute to the skeletal phenotype of CLS.