Jia Yonghui, Loison Fabien, Hattori Hidenori, Li Yitang, Erneux Christophe, Park Shin-Young, Gao Chong, Chai Li, Silberstein Leslie E, Schurmans Stephane, Luo Hongbo R
Department of Pathology, Dana-Farber/Harvard Cancer Center, Children's Hospital Boston and Joint Program in Transfusion Medicine, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4739-44. doi: 10.1073/pnas.0800218105. Epub 2008 Mar 13.
Inositol trisphosphate 3-kinase B (InsP3KB) belongs to a family of kinases that convert inositol 1,4,5-trisphosphate (Ins(1,4,5)P3 or IP3) to inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4). Previous studies have shown that disruption of InsP3KB leads to impaired T cell and B cell development as well as hyperactivation of neutrophils. Here, we demonstrate that InsP3KB is also a physiological modulator of myelopoiesis. The InsP3KB gene is expressed in all hematopoietic stem/progenitor cell populations. In InsP3KB null mice, the bone marrow granulocyte monocyte progenitor (GMP) population was expanded, and GMP cells proliferated significantly faster. Consequently, neutrophil production in the bone marrow was enhanced, and the peripheral blood neutrophil count was also substantially elevated in these mice. These effects might be due to enhancement of PtdIns(3,4,5)P3/Akt signaling in the InsP3KB null cells. Phosphorylation of cell cycle-inhibitory protein p21(cip1), one of the downstream targets of Akt, was augmented, which can lead to the suppression of the cell cycle-inhibitory effect of p21.
肌醇三磷酸3激酶B（InsP3KB）属于一类激酶，可将肌醇1,4,5-三磷酸（Ins(1,4,5)P3或IP3）转化为肌醇1,3,4,5-四磷酸（Ins(1,3,4,5)P4）。先前的研究表明，InsP3KB的缺失会导致T细胞和B细胞发育受损以及中性粒细胞过度活化。在此，我们证明InsP3KB也是骨髓生成的生理调节因子。InsP3KB基因在所有造血干/祖细胞群体中均有表达。在InsP3KB基因敲除小鼠中，骨髓粒细胞-单核细胞祖细胞（GMP）群体扩大，且GMP细胞增殖明显加快。因此，这些小鼠骨髓中的中性粒细胞生成增强，外周血中性粒细胞计数也大幅升高。这些效应可能是由于InsP3KB基因敲除细胞中磷脂酰肌醇(3,4,5)三磷酸/蛋白激酶B（PtdIns(3,4,5)P3/Akt）信号增强所致。细胞周期抑制蛋白p21(cip1)（Akt的下游靶点之一）的磷酸化增强，这可导致p21的细胞周期抑制作用受到抑制。
