ROLE OF G-KINASE IN DIFFERENTIATION--USE OF HL-60 MUTANT
G-激酶在分化中的作用--HL-60 突变体的使用
基本信息
- 批准号:3080020
- 负责人:
- 金额:$ 8.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1990
- 资助国家:美国
- 起止时间:1990-08-16 至 1995-07-31
- 项目状态:已结题
- 来源:
- 关键词:autoradiography cell differentiation complementary DNA cyclic AMP cyclic GMP enzyme substrate gel electrophoresis high performance liquid chromatography molecular cloning mutant myeloid stem cell phosphoproteins phosphorylation protein biosynthesis protein kinase protein structure function tissue /cell culture transfection
项目摘要
The abnormal cells from patients with myelodysplastic syndromes and acute
myelogenous leukemias fail to differentiate normally. A better
understanding of the biochemical events regulating myeloid cell
differentiation could potentially lead to more specific therapies of these
disorders. The human promyelocytic cell line HL-60 provides the opportunity
to study myeloid cell differentiation in vitro as it differentiates into
granulocytes in response to several inducers, including dimethylsulfoxide
(DMSO), and cAMP- and cGMP-elevating agents. Since cAMP and cGMP exert
their effects almost exclusively through their respective protein kinases,
it appears that differentiation of HL-60 cells can be induced by
phosphorylation of key regulatory protein(s). The PI has recently isolated
stable mutant HL-60 sublines which are resistant to the differentiating
effects of elevated cGMP concentrations but differentiate normally in re-
sponse to other inducing agents including DMSO and 8-Br-cAMP. Preliminary
characterization of these mutants indicates a defect in phosphorylation of
a cGMP-dependent protein kinase substrate (or substrates). The three major
goals of this proposal are: (i) to identify the proteins phosphorylated in
wild type HL-60 cells during cGMP-induced differentiation that are not
phosphorylated in the mutant HL-60 cells; (ii) to purify and partially
sequence one or several of these phosphoproteins; and (iii) to isolate a
cDNA clone of one of the phosphoproteins. The proteins will be identified
by 2-D PAGE/autoradiography and selected ones will be purified using a
combination of radio-HPLC and PAGE/autoradiography. The partial amino acid
sequence of the proteins will provide information about their physiological
function and will allow synthesis of degenerative oligonucleotides and
peptide specific antibodies. A cDNA clone and peptide-specific antibodies
will allow study of the regulation of the phosphoprotein's synthesis during
differentiation of HL-60 cells and of the molecular defect in the mutant
HL-60 cells. The cloned gene will be transfected into the mutant cells to
determine if it will correct their defect and the phosphoprotein will be
microinjected into wild type HL-60 cells to determine if it is sufficient
to induce differentiation. These studies will provide the PI with training
in protein biochemistry and molecular biology and lay the foundation for
future studies in patients with myelodysplastic syndromes and acute
myelogenous leukemias.
骨髓增生异常综合征和急性骨髓增生异常综合征患者的异常细胞
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RENATE B PILZ其他文献
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{{ truncateString('RENATE B PILZ', 18)}}的其他基金
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