Receptor-mediated signalings-regulating proliferation, differentiation and neoplastic transformation of hematopoietic cells

受体介导的信号传导——调节造血细胞的增殖、分化和肿瘤转化

基本信息

批准号：
09470231
负责人：
KANAKURA Yuzuru
金额：
$ 9.09万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470231/
关键词：
c-kit c-mpl tyrosine kinase thrombopoietin signal transduction proliferation differentiation ras ras 造血因子受容体増殖分化腫瘍

项目摘要

The c-kit receptor tyrosine kinase (KIT) and its ligand, stem cell factor (SCF) transduce crucial signals in hematopoietic cells. We revealed that two point mutations, Val559→Gly (G559) mutation in the juxtamembrane domain and Asp814→Val (V814) mutation in the kinase domain, lead to constitutive and oncogenic activation of KIT. In order to determine as to which portion of mutant KITs is indispensable for receptor dimerization or self-association in the absence of SCF, we have constructed a series of deletion and chimeric mutants of KIT, including the extracellular domain truncated type KIT and chimeric type KIT in which extracellular and transmembrane domains are replaced by src myristylation signal peptide. By using murine interleukin (IL)-3-dependent Ba/F3 cells that were subjected to transfection of various c-kit genes, we showed that the constituvely activating mutations at both the juxtamembrane and kinase domains of KIT may not necessarily require their extracellular and transmem … More brane domains for their formation of receptor self-association, and that the receptor self-association of mutant KIT may be important for activation of downstream effectors that are required for factor-independent growth and tumorigenicity.In addition to the SCF/KIT system, thrombopoietin (TPO)/c-mpl system also plays a fundamental role in hematopoiesis. In an effort to clarify the mechanisms of TPO-induced proliferation and differentiation, c-mpl was introduced into human IL-3-dependent F-36P cells. F-36P-mpl cells were found to proliferate and differentiate at a high rate into mature megakaryocytes in response to TPO. By using dominant-negative (dn) forms of STATs and ras, it was suggested that TPO-induced proliferation may be mediated through activation of STAT5 and ras, and that prolonged ras activation may be involved in TPO-induced megakaryocytic differentiation. Furthermore, we found that STAT5, in addition to ras signaling, appeared to mediate transcriptional regulation of cyclin D1 during cytokine-dependent growth in hematopoietic cells. Less

C-KIT受体酪氨酸激酶（试剂盒）及其配体干细胞因子（SCF）在造血细胞中的透射信号，Val559→Gly（G559）突变（G559）突变激酶结构域中的突变，导致试剂盒的构成性和致癌性激活，以用于受体二聚体或自我关联，在没有SCF的情况下，我们已经构建了一系列的删除和嵌合物突变体在其中使用鼠白介素（IL）-3-二足体BA/F3细胞替代了细胞外和跨膜INS的试剂盒。试剂盒的近去膜和激酶结构域可能不会不需要割让，需要其细胞外和传输……更多的Brene域才能形成受体自我结合，而Mutt套件的受体自我遵循对于激活下游效应物的受体自我遵循的能力很重要在SCF/KIT系统中，非因子独立和肿瘤型，血小板蛋白（TPO）/C-MPL系统在造血中也起着基本作用。被引入人IL-3多种F-36p细胞中。通过STAT5和RAS的激活，延长的RAS激活可能与TPO诱导的巨核细胞分化有关。较少的。