ID PROTEIN FAMILY EXPRESSION AND FUNCTION IN PROSTATE CANCER
ID 蛋白家族在前列腺癌中的表达和功能
基本信息
- 批准号:8166160
- 负责人:
- 金额:$ 23.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
The heterogeneity of prostate cancer suggests that the pathways that lead to malignant transformation are not uniform but certain genetic alterations and pathways may be common in the initiation leading to malignancy. The progression to invasive carcinoma is characterized by de-regulation of differentiation process, leading to an increase in the proliferation and a corresponding decrease in apoptosis. The transcription factor family, which is known to regulate both these processes, is the basic helix-loop-helix bHLH family. The Id (Inhibitor of differentiation) proteins function as natural negative regulators of bHLH protein activity through the formation of inactive heterodimers with bHLH transcription factors. Consequently, Id gene expression is elevated in undifferentiated, proliferating and tumor cells. The Id proteins also function at multiple levels and its interactions may not be limited to bHLH proteins. Over-expression of Id proteins results in apoptosis and/or cell proliferation. The ability of Id to stimulate the cell cycle, activate telomerase and immortalize cell types suggests that Id proteins may act as oncogenes or cooperating oncogenes. Our recent results suggest that the functions of Id proteins in prostate cancer cell lines are non-redundant. Id1, Id2 and Id3 are potential oncogenes or cooperating oncogenes and surprisingly, Id4 acts as a tumor suppressor. Id1 and Id3 target cell proliferation pathways, Id2 targets apoptosis and Id4 acts as a tumor suppressor by inducing the expression of p53, E-cadherin and androgen receptor (AR) in AR-ve prostate cancer cell line. Interestingly, Id3 copy number is also increased in DU145 prostate cancer cell line. Hence Id proteins represent a new paradigm in prostate cancer biology that needs to be carefully examined. Increased expression of Id1, Id2 and Id3 proteins has been reported in primary human tumors including human prostate and cultured tumor cells, whereas Id4 expression is lost in many cancer cell lines and tissues possibly due to promoter hypermethylation.
Preliminary studies have demonstrated that loss of function of Id1/ Id3 and Id2 blocks proliferation and apoptosis respectively, whereas gain of Id4 functions initiates an epithelial phenotype and re-emergence of AR receptor expression in model prostate cancer cell lines. The present study is therefore designed to test the hypothesis that "Id genes (Id1, Id2, Id3 and Id4) have non-redundant functions and their expression levels, copy number changes (Id3) and promoter methylation status (id4) are sensitive prognostic markers strong therapeutic targets for the management of the disease". The novel ideas that are being pursued in this proposal are the copy number changes in Id3 and the role of Id4 as a tumor suppressor in prostate cancer.
该副本是利用众多研究子项目之一
由NIH/NCRR资助的中心赠款提供的资源。子弹和
调查员(PI)可能已经从其他NIH来源获得了主要资金,
因此可以在其他清晰的条目中代表。列出的机构是
对于中心,这不一定是调查员的机构。
前列腺癌的异质性表明,导致恶性转化的途径并不统一,但某些遗传改变和途径在导致恶性肿瘤的开始时可能很常见。浸润性癌的进展为特征是分化过程的下调,导致增殖增加和凋亡的相应减少。转录因子家族(已知可以调节这两个过程)是基本的Helix-loop-helix bhlh家族。 ID(分化的抑制剂)蛋白通过形成具有BHLH转录因子的无活性异二聚体的自然负调节剂。因此,在未分化,增殖和肿瘤细胞中,ID基因表达升高。 ID蛋白还可以在多个层次上发挥作用,其相互作用可能不限于BHLH蛋白。 ID蛋白的过表达导致细胞凋亡和/或细胞增殖。 ID刺激细胞周期,激活端粒酶和永生的细胞类型的能力表明,ID蛋白可以充当肿瘤基因或合作致癌基因。我们最近的结果表明,ID蛋白在前列腺癌细胞系中的功能是非冗余的。 ID1,ID2和ID3是潜在的癌基因或合作的癌基因,令人惊讶的是,ID4充当肿瘤抑制剂。 ID1和ID3靶细胞增殖途径,ID2靶向细胞凋亡,而ID4通过诱导p53,e-钙粘蛋白和雄激素受体(AR)在AR-VE PROSTATE癌细胞系中的表达来充当肿瘤抑制器。 有趣的是,在DU145前列腺癌细胞系中,ID3拷贝数也增加。 因此,ID蛋白代表了前列腺癌生物学的新范式,需要仔细检查。 在包括人前列腺和培养的肿瘤细胞在内的原发性肿瘤中,ID1,ID2和ID3蛋白的表达增加了,而在许多癌细胞系和组织中,ID4表达可能由于启动子高甲基化而丧失。
初步研究表明,ID1/ ID3和ID2的功能丧失分别阻止了增殖和凋亡,而ID4功能的增益启动了模型前列腺癌细胞系中AR受体表达的上皮表型和重新出现。因此,本研究旨在检验以下假设:“ ID基因(ID1,ID2,ID3和ID4)具有非冗余功能及其表达水平,拷贝数变化(ID3)和启动子甲基化状态(ID4)是敏感的预后标记,可用于治疗该疾病的治疗目标。 该提案中正在提出的新思想是ID3中的拷贝数变化以及ID4作为前列腺癌中肿瘤抑制剂的作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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数据更新时间:2024-06-01
JAIDEEP CHAUDHARY的其他基金
Altered Immune/Inflammatory Pathway in Racially Diverse Prostate Cancers
不同种族前列腺癌中免疫/炎症途径的改变
- 批准号:85440448544044
- 财政年份:2012
- 资助金额:$ 23.92万$ 23.92万
- 项目类别:
ID PROTEIN FAMILY EXPRESSION AND FUNCTION IN PROSTATE CANCER
ID 蛋白家族在前列腺癌中的表达和功能
- 批准号:83571228357122
- 财政年份:2011
- 资助金额:$ 23.92万$ 23.92万
- 项目类别:
Inhibitor of Differentiation Gene Expression and Function in Prostate Cells
前列腺细胞分化基因表达和功能的抑制剂
- 批准号:85378408537840
- 财政年份:2009
- 资助金额:$ 23.92万$ 23.92万
- 项目类别:
Inhibitor of Differentiation Gene Expression and Function in Prostate Cells
前列腺细胞分化基因表达和功能的抑制剂
- 批准号:77273047727304
- 财政年份:2009
- 资助金额:$ 23.92万$ 23.92万
- 项目类别:
Inhibitor of Differentiation Gene Expression and Function in Prostate Cells
前列腺细胞分化基因表达和功能的抑制剂
- 批准号:81931598193159
- 财政年份:2009
- 资助金额:$ 23.92万$ 23.92万
- 项目类别:
Inhibitor of Differentiation Gene Expression and Function in Prostate Cells
前列腺细胞分化基因表达和功能的抑制剂
- 批准号:78954847895484
- 财政年份:2009
- 资助金额:$ 23.92万$ 23.92万
- 项目类别:
Inhibitor of Differentiation Gene Expression and Function in Prostate Cells
前列腺细胞分化基因表达和功能的抑制剂
- 批准号:83251848325184
- 财政年份:2009
- 资助金额:$ 23.92万$ 23.92万
- 项目类别:
ID PROTEIN FAMILY EXPRESSION AND FUNCTION IN PROSTATE CANCER
ID 蛋白家族在前列腺癌中的表达和功能
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- 项目类别:
ID PROTEIN FAMILY EXPRESSION AND FUNCTION IN PROSTATE CANCER
ID 蛋白家族在前列腺癌中的表达和功能
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- 财政年份:2008
- 资助金额:$ 23.92万$ 23.92万
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