p85β regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis
p85β regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis
复制标题
DOI：
10.1182/blood-2011-05-355602
复制
发表时间：
2012-04-26
期刊：
影响因子：
20.3
通讯作者：
Kapur, Reuben
中科院分区：
文献类型：
--
作者：
Krishnan, Subha;Mali, Raghuveer Singh;Kapur, Reuben
我们发现p85 α的缺失会抑制肥大细胞的生长和成熟，而p85 β的缺失则会增强这一过程。虽然在p85 α(-/-)细胞中恢复p85 α的表达可以恢复这些功能，但过度表达p85 β具有相反的效果。同样，WT肥大细胞中p85 β的过表达通过抑制小眼转录因子的表达来抑制kit诱导的增殖和il -3介导的成熟。由于p85 α和p85 β的n端序列不同，由p85 α和/或p85 β的氨基端或羧基端组成的嵌合蛋白不能挽救p85 α(-/-)细胞的生长缺陷，这表明这些结构域之间的合作是正常肥大细胞功能的基础。p85 β受损配体的缺失诱导KIT受体内化及其过表达增强了这一过程，部分原因是相对于p85 α， c-Cbl与p85 β的结合增加。在体内，p85 β的缺失导致肥大细胞增加，过表达p85 β的细胞骨髓移植导致一些组织肥大细胞显著减少。p85 β的过表达在体外抑制了表达kit的致癌细胞的生长，并延长了白血病小鼠的体内存活时间。因此，p85 α和p85 β在髓系源性肥大细胞中对SCF和kit诱导的致癌信号有不同的调节作用。(血。2012;119 (17):3951 - 3961)
We show that loss of p85 alpha inhibits the growth and maturation of mast cells, whereas loss of p85 beta enhances this process. Whereas restoring the expression of p85 alpha in P85 alpha(-/-) cells restores these functions, overexpression of p85 beta has the opposite effect. Consistently, overexpression of p85 beta in WT mast cells represses KIT-induced proliferation and IL-3-mediated maturation by inhibiting the expression of Microphthalmia transcription factor. Because p85 alpha and p85 beta differ in their N-terminal sequences, chimeric proteins consisting of amino or carboxy-terminal of p85 alpha and/or p85 beta do not rescue the growth defects of p85 alpha(-/-) cells, suggesting cooperation between these domains for normal mast cell function. Loss of p85 beta impaired ligand induced KIT receptor internalization and its overexpression enhanced this process, partly because of increased binding of c-Cbl to p85 beta relative to p85 alpha. In vivo, loss of p85 beta resulted in increased mast cells, and bone marrow transplantation of cells overexpressing p85 beta resulted in significant reduction in some tissue mast cells. Overexpression of p85 beta suppressed the growth of oncogenic KIT-expressing cells in vitro and prolonged the survival of leukemic mice in vivo. Thus, p85 alpha and p85 beta differentially regulate SCF and oncogenic KIT-induced signals in myeloid lineage-derived mast cells. (Blood. 2012;119(17):3951-3961)