miR-582 negatively regulates pre-B cell proliferation and survival through targeting Hif1α and Rictor.
miR-582 negatively regulates pre-B cell proliferation and survival through targeting Hif1α and Rictor.
复制标题
miR-582 通过靶向 Hif1α 和 Rictor 负调节前 B 细胞增殖和存活
DOI：
10.1038/s41419-022-04560-y
复制
发表时间：
2022-02-03
影响因子：
9
通讯作者：
Han H
中科院分区：
文献类型：
--
作者：
Li X;Zhang Y;Zheng M;Cao X;Guo M;Gao X;Han H
骨髓（BM）中的B细胞发育是一个多阶段的过程，涉及pro-B、pre-B、未成熟B和成熟B细胞，其中pre-B细胞经历旺盛的增殖、分化、凋亡和基因重排。虽然参与前 B 细胞发育的几种信号通路已被阐明，但调节前 B 细胞增殖和存活的详细内在机制尚未完全了解。在当前的研究中，我们报告 miR-582 调节前 B 细胞增殖和存活。 miR-582 在前 B 细胞中富集。竞争性骨髓移植表明，小鼠体内 miR-582 的缺失以细胞自主方式扩大了骨髓前 B 细胞群。我们发现，强制 miR-582 过表达抑制前 B 细胞增殖和存活，而 siRNA 下调 miR-582 显着促进体外前 B 细胞增殖和存活。正如报告基因检测所示，我们确定 Hif1α 和 Rictor 是前 B 细胞中 miR-582 的真实靶标。此外，miR-582 过表达降低了 Hif1α 及其下游分子 Glut1 的表达，以及 Rictor 和 mTORC2 活性，如 AKT 和 FoxO1 磷酸化减弱所示，而 miR-582 敲低则表现出相反的效果。 Hif1α 和 Rictor 抑制剂消除了 miR-582 敲低诱导的 pre-B 增殖和存活增加。 miR-582 通过同时靶向调节早期 B 细胞发育代谢的 Hif1α 和 mTORC2 信号传导，充当前 B 细胞增殖和存活的负调节因子。
B cell development in bone marrow (BM) is a multi-staged process involving pro-B, pre-B, immature B, and mature B cells, among which pre-B cells undergo vigorous proliferation, differentiation, apoptosis, and gene rearrangement. While several signaling pathways participate in pre-B cell development have been clarified, detailed intrinsic mechanisms regulating pre-B cell proliferation and survival have not been fully understood. In the current study, we report that miR-582 regulates pre-B cell proliferation and survival. miR-582 is enriched in pre-B cells. Deletion of miR-582 in mice expanded the BM pre-B cell population in a cell-autonomous manner as shown by competitive BM transplantation. We show that forced miR-582 overexpression inhibited pre-B cell proliferation and survival, whereas downregulation of miR-582 by siRNA significantly promoted pre-B cell proliferation and survival in vitro. We identified that Hif1α and Rictor are authentic targets of miR-582 in pre-B cells as shown by reporter assays. Moreover, miR-582 overexpression reduced the expression of Hif1α and its downstream molecule Glut1, as well as Rictor and mTORC2 activity as shown by attenuated AKT and FoxO1 phosphorylation, while miR-582 knockdown showed opposite effects. miR-582 knockdown-induced increases in pre-B proliferation and survival was abrogated by Hif1α and Rictor inhibitors. Together, miR-582 functions as a negative regulator of pre-B cell proliferation and survival by simultaneously targeting Hif1α and mTORC2 signaling that regulates metabolism in early B cell development.
登录
查看更多内容
影响因子：
3.3
作者：
Tian Y;Guan Y;Su Y;Luo W;Yang G;Zhang Y
通讯作者：
Zhang Y
DOI：
10.1084/jem.20092210
发表时间：
2010-05-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Allende ML;Tuymetova G;Lee BG;Bonifacino E;Wu YP;Proia RL
通讯作者：
Proia RL
影响因子：
11.4
作者：
Venigalla, Ram K. C.;McGuire, Victoria A.;Clarke, Rosemary;Patterson-Kane, Janet C.;Najafov, Ayaz;Toth, Rachel;McCarthy, Pierre C.;Simeons, Frederick;Stojanovski, Laste;Arthur, J. Simon C.
通讯作者：
Arthur, J. Simon C.
DOI：
10.4049/jimmunol.0800167
发表时间：
2010-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kojima H;Kobayashi A;Sakurai D;Kanno Y;Hase H;Takahashi R;Totsuka Y;Semenza GL;Sitkovsky MV;Kobata T
通讯作者：
Kobata T
影响因子：
4.4
作者：
Han, H;Tanigaki, K;Honjo, T
通讯作者：
Honjo, T