TRANSCRIPTION FACTOR REGULATION BY THE BCR/ABL ONCOGENE

BCR/ABL 癌基因对转录因子的调节

基本信息

  • 批准号:
    6952413
  • 负责人:
  • 金额:
    $ 31.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2002
  • 资助国家:
    美国
  • 起止时间:
    2002-07-01 至 2007-06-30
  • 项目状态:
    已结题

项目摘要

Transcription factor regulation by the BCR/ABL oncogene Human hematological malignancies are characterized by well- defined genetic abnormalities responsible for the generation of autonomous growth signals or the aberrant transduction of these signals from the cytoplasm to the nucleus. The BCR/ABL oncoproteins, the leukemia-specific gene products of the Philadelphia chromosome (Ph1) translocation, induce and maintain the leukemic phenotype through their deregulated tyrosine kinase activity; such activity is essential for recruitment and activation of multiple pathways that transduce signals leading to growth factor-independent proliferation, inhibition of apoptosis, and altered differentiation of myeloid precursor cells. The mechanisms of activation of the cytoplasmic downstream effectors of BCR/ABL are understood in some detail, but much less is known on the pathways leading to transcription factor regulation. This application focuses on investigating the BCR/ABL-dependent pathways leading to changes in the expression of c-Myb and C/EBPalpha, two transcription factors involved in the regulation of proliferation, survival, and differentiation of hematopoietic cells. Specifically, we will: 1) Investigate mechanisms of the enhanced expression/activity of c-Myb by: a. determining sequence requirements and enzymatic pathways that regulate ubiquitination and/or proteasome-dependent degradation of c-Myb in normal and BCR/ABL-expressing hematopoietic cells. b. identifying the interacting proteins promoting the ubiquitin/proteasome-dependent degradation of c-Myb. c. determining whether the activity of proteins promoting c-Myb degradation is modulated in BCR/ABL-expressing cells. 2) Assessing the effects of degradation-resistant c-Myb mutants on proliferation, survival, and differentiation of hematopoietic cells. 3) Assessing leukemic samples for the presence of c-myb mutations within domains involved in protein degradation. 4) Investigating the mechanisms whereby BCR/ABL suppresses the expression of the granulocytic differentiation regulator C/EBPalpha.
BCR/ABL癌基因对转录因子的调节人类血液恶性肿瘤的特征在于明确的遗传异常,其导致自主生长信号的产生或这些信号从细胞质到细胞核的异常转导。 BCR/ABL癌蛋白是费城染色体(Ph 1)易位的白血病特异性基因产物,通过其失调的酪氨酸激酶活性诱导和维持白血病表型;这种活性对于募集和激活多种途径至关重要,这些途径抑制导致生长因子非依赖性增殖的信号,抑制凋亡和改变骨髓前体细胞的分化。 BCR/ABL细胞质下游效应物的激活机制已被详细了解,但对导致转录因子调节的途径知之甚少。 本申请的重点是研究BCR/ABL依赖性途径导致c-Myb和C/EBPalpha表达的变化,这两种转录因子参与造血细胞增殖、存活和分化的调节。 具体而言,我们将:1)通过以下方式研究c-Myb的表达/活性增强的机制:a.确定正常造血细胞和表达BCR/ABL的造血细胞中调节c-Myb的泛素化和/或蛋白酶体依赖性降解的序列要求和酶途径。B.鉴定促进c-Myb的泛素/蛋白酶体依赖性降解的相互作用蛋白。C.确定在表达BCR/ABL的细胞中促进c-Myb降解的蛋白质的活性是否受到调节。2)评估抗降解c-Myb突变体对造血细胞增殖、存活和分化的影响。3)评估白血病样本中蛋白质降解相关区域内c-myb突变的存在。4)研究BCR/ABL抑制粒细胞分化调节因子C/EBPalpha表达的机制。

项目成果

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BRUNO CALABRETTA其他文献

BRUNO CALABRETTA的其他文献

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{{ truncateString('BRUNO CALABRETTA', 18)}}的其他基金

A novel strategy for transcriptional reprogramming of lymphoid leukemia cells
淋巴细胞白血病细胞转录重编程的新策略
  • 批准号:
    10392174
  • 财政年份:
    2022
  • 资助金额:
    $ 31.44万
  • 项目类别:
A novel strategy for transcriptional reprogramming of lymphoid leukemia cells
淋巴细胞白血病细胞转录重编程的新策略
  • 批准号:
    10543999
  • 财政年份:
    2022
  • 资助金额:
    $ 31.44万
  • 项目类别:
Targeting CDK6 expression/activity in Ph+ and Ph1-like acute lymphoblastic leukemia (ALL)
靶向 Ph 和 Ph1 样急性淋巴细胞白血病 (ALL) 中的 CDK6 表达/活性
  • 批准号:
    10437005
  • 财政年份:
    2021
  • 资助金额:
    $ 31.44万
  • 项目类别:
Targeting CDK6 expression/activity in Ph+ and Ph1-like acute lymphoblastic leukemia (ALL)
靶向 Ph 和 Ph1 样急性淋巴细胞白血病 (ALL) 中的 CDK6 表达/活性
  • 批准号:
    10317798
  • 财政年份:
    2021
  • 资助金额:
    $ 31.44万
  • 项目类别:
Targeting CDK6 expression/activity in Ph+ and Ph1-like acute lymphoblastic leukemia (ALL)
靶向 Ph 和 Ph1 样急性淋巴细胞白血病 (ALL) 中的 CDK6 表达/活性
  • 批准号:
    10652495
  • 财政年份:
    2021
  • 资助金额:
    $ 31.44万
  • 项目类别:
The role of chromatin structure in differentiation of hematopoietic stem cells
染色质结构在造血干细胞分化中的作用
  • 批准号:
    9037410
  • 财政年份:
    2016
  • 资助金额:
    $ 31.44万
  • 项目类别:
Targeting the C/EBPalpha-Gfi-pathway in CML stem cells
靶向 CML 干细胞中的 C/EBPalpha-Gfi 通路
  • 批准号:
    8737206
  • 财政年份:
    2013
  • 资助金额:
    $ 31.44万
  • 项目类别:
Targeting the C/EBPalpha-Gfi-pathway in CML stem cells
靶向 CML 干细胞中的 C/EBPalpha-Gfi 通路
  • 批准号:
    8451043
  • 财政年份:
    2013
  • 资助金额:
    $ 31.44万
  • 项目类别:
Targeting the C/EBPalpha-Gfi-pathway in CML stem cells
靶向 CML 干细胞中的 C/EBPalpha-Gfi 通路
  • 批准号:
    9120811
  • 财政年份:
    2013
  • 资助金额:
    $ 31.44万
  • 项目类别:
TRANSCRIPTION FACTOR REGULATION BY THE BCR/ABL ONCOGENE
BCR/ABL 癌基因对转录因子的调节
  • 批准号:
    6460479
  • 财政年份:
    2002
  • 资助金额:
    $ 31.44万
  • 项目类别:

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  • 批准号:
    6238317
  • 财政年份:
    1997
  • 资助金额:
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