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c-Src 激酶通过增强 STAT1 稳定性来抑制成骨分化。

c-Src kinase inhibits osteogenic differentiation via enhancing STAT1 stability.

机构信息

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Department of Vascular Biology, Boston Children's Hospital, Boston, MA, United States of America.

出版信息

PLoS One. 2020 Nov 12;15(11):e0241646. doi: 10.1371/journal.pone.0241646. eCollection 2020.

DOI:10.1371/journal.pone.0241646
PMID:33180789
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7660501/
Abstract

The proto-oncogene Src is ubiquitously expressed and is involved in cellular differentiation. However, the role of Src in embryonic stem (ES) cell osteogenic differentiation is largely unknown. Using the small molecule inhibitor PP2, c-Src specific siRNAs, and tet-inducible lentiviral vectors overexpressing active c-Src, we delineated an inhibitory role of c-Src in osteogenic differentiation of mouse embryonic stem cells (mESCs) and mouse MC3T3-E1s preosteoblasts. Active c-Src was shown to restrict the nuclear residency of Runt-related transcription factor 2 (Runx2) and its transcriptional activity with no detectable effect on Runx2 expression level. Furthermore, we showed Signal Transducer and Activator of Transcription 1 (STAT1) was indispensable to the inhibitory role of c-Src on Runx2 nuclear localization. Specifically, higher levels of active c-Src increased STAT1 half-life by inhibiting its proteasomal degradation, thereby increasing the cytoplasmic abundance of STAT1. More abundant cytoplasmic STAT1 bound and anchored Runx2, which restricted its nucleocytoplasmic shuttling and ultimately reduced Runx2 transcriptional activity. Collectively, this study has defined a new mechanism by which c-Src inhibits the transcriptional regulation of osteogenesis from mESCs in vitro.

摘要

原癌基因 Src 广泛表达，并参与细胞分化。然而，Src 在胚胎干细胞 (ES) 细胞成骨分化中的作用在很大程度上尚不清楚。使用小分子抑制剂 PP2、c-Src 特异性 siRNA 和 tet 诱导的过表达活性 c-Src 的慢病毒载体，我们描绘了 c-Src 在小鼠胚胎干细胞 (mESCs) 和小鼠 MC3T3-E1 前成骨细胞的成骨分化中的抑制作用。活性 c-Src 被证明限制了 Runt 相关转录因子 2 (Runx2) 的核定位及其转录活性，而对 Runx2 表达水平没有可检测到的影响。此外，我们表明信号转导和转录激活因子 1 (STAT1) 对于 c-Src 对 Runx2 核定位的抑制作用是必不可少的。具体而言，更高水平的活性 c-Src 通过抑制其蛋白酶体降解来增加 STAT1 的半衰期，从而增加细胞质中 STAT1 的丰度。更多的细胞质 STAT1 结合并锚定 Runx2，限制其核质穿梭，最终降低 Runx2 的转录活性。总之，这项研究定义了一种新的机制，通过该机制，c-Src 抑制了体外 mESCs 成骨分化的转录调控。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0f0/7660501/3dd7f92ea8fb/pone.0241646.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0f0/7660501/9b46d4398568/pone.0241646.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0f0/7660501/f6afc34d24ae/pone.0241646.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0f0/7660501/bd267e6f92b3/pone.0241646.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0f0/7660501/3dd7f92ea8fb/pone.0241646.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0f0/7660501/9b46d4398568/pone.0241646.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0f0/7660501/f6afc34d24ae/pone.0241646.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0f0/7660501/bd267e6f92b3/pone.0241646.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0f0/7660501/3dd7f92ea8fb/pone.0241646.g004.jpg

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