TGFB SIGNALING IN PROSTATE CANCER CELLS

前列腺癌细胞中的 TGFB 信号传导

• 批准号: 7645117
• 负责人: SHAFIQ AHMED KHAN
• 金额: $ 23.37万
• 依托单位: CLARK ATLANTA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7645117
• 关键词: Affect; African American; Aftercare; Age; Antibodies; Applications Grants; Benign; Binding; Biological Assay; Cell Extracts; Cell Line; Cell Proliferation; Cells; Complex; Consensus; Coupled; DNA Binding; DU145; Development; Dimerization; Disease; Disease Progression; Disruption; Dominant-Negative Mutation; Electrophoretic Mobility Shift Assay; Elements; Epithelial Cell Proliferation; Epithelial Cells; Family; Family member; Gene Cluster; Gene Expression; Genes; Hand; Hypertension; Hypertrophy; In Vitro; Incidence; Individual; Infection; Inhibition of Cell Proliferation; JUN gene; Kidney Diseases; Lead; MAPK8 gene; MAPK9 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mitogen-Activated Protein Kinases; N-terminal; Neoplasm Metastasis; Organ; PC3 cell line; Pathway interactions; Pattern; Phase; Phosphorylation; Phosphotransferases; Play; Polymerase Chain Reaction; Prostate; Protein Family; Protein Isoforms; Protein Overexpression; Proteins; Rate; Regulation; Research Design; Resistance development; Role; Signal Transduction; Site; Smad Proteins; Smad protein; Staging; Stream; System; TGFB1 gene; Testing; Time; Transcription Factor AP-1; Transforming Growth Factors; Tumor Suppressor Proteins; Western Blotting; angiogenesis; autocrine; base; cancer cell; cell transformation; design; dimer; jun D Proteins; member; men; neoplastic cell; novel; receptor; research study; response; stable cell line; transcription factor; vector

Transforming growth factor-p (TGFp) inhibits the proliferation of epithelial cells in the prostate gland and acts as a tumor suppressor in the earlier stages of prostate cancer. However, prostate cancer cells develop resistance to TGFp inhibitory effects during the later stages of the disease. At that time, TGFp promotes angiogenesis and metastasis and hence is associated with the development of more aggressive form of this disease. We hypothesize that TGFp hypersecretion coupled with the loss of its inhibitory effects on proliferation leads to an earlier on set of more aggressive prostate cancers in African-American men. The proposed studies are designed to test this hypothesis. The cellular mechanisms involved in the development of resistance to inhibitory effects of TGFp on proliferation are not known but may involve components of TGFp signaling in transformed cells. Our preliminary studies show that TGFp inhibits proliferation of prostate cancer cell line DU145 but has no effect on proliferation of PC3 and LnCaP cells. Inhibition of proliferation in response to TGFp was associated with rapid decrease in the levels of Jun D in DU145 cells and overexpression of Jun D in these cells resulted in increased proliferation. On the other hand, over-expression of c-Jun resulted in decreased proliferation rate and increased sensitivity to TGFp. Our results suggest that decreasing Jun D levels may enhance c-Jun binding at the AP-1 site in TGFp treated cells to mediate inhibitory effects on cell proliferation. The proposed studies are designed to determine the role of TGFp during different stages of prostate cancer development and the role of c-Jun and Jun D in TGFp signaling during different stages and will focus on the following specific aims: 1. We will determine the expression patterns of TGFp isoforms, TGFp receptors, AP-1 and SMAD proteins in normal prostate epithelial cells and prostate cancer cells representing different stages of the disease, and their regulation by TGFp. 2. We will determine DMA binding activity of AP-1 and SMAD proteins in prostate cancer cells after treatment with TGFp and determine the roles of c-Jun and Jun D in prostate cancer cell proliferation. 3. We will also study the effects of TGFp on JNK activation and phosphorylation of Jun family members and determine their effects on cell proliferation. We will analyze c-Jun dependent gene expression in prostate cells in response to TGFp to identify down-stream signaling components involved in inhibition of cell proliferation.

转化生长因子-P（TGFP）抑制前列腺中上皮细胞的增殖，并作用 在前列腺癌的早期阶段作为肿瘤抑制剂。但是，前列腺癌细胞发展 疾病后期对TGFP抑制作用的抵抗力。当时，TGFP促进 血管生成和转移，因此与更具侵略性形式的发展有关 疾病。我们假设TGFP高血压以及其对其对抑制作用的丧失对 扩散会导致在非裔美国人中的一系列更具侵略性的前列腺癌。这 拟议的研究旨在检验这一假设。发育中涉及的细胞机制 尚不清楚TGFP对TGFP对增殖的抑制作用的抗性，但可能涉及 转化细胞中的TGFP信号传导。我们的初步研究表明，TGFP抑制前列腺的增殖 癌细胞系DU145，但对PC3和LNCAP细胞的增殖没有影响。抑制增殖 对TGFP的响应与DU145细胞中Jun D的水平迅速降低和过表达有关 这些细胞中的6月D导致增殖增加。另一方面，过表达 C-Jun导致增殖率降低，对TGFP的敏感性提高。我们的结果表明 降低的6月D水平可能会增强TGFP处理细胞中AP-1位点的C-JUN结合以介导 对细胞增殖的抑制作用。拟议的研究旨在确定TGFP的作用 在前列腺癌发展的不同阶段以及C-Jun和Jun D在TGFP信号中的作用 在不同的阶段，将关注以下特定目的：1。我们将确定表达式 正常前列腺上皮细胞中TGFP同工型，TGFP受体，AP-1和SMAD蛋白的模式 前列腺癌细胞代表了该疾病的不同阶段，并由TGFP调节。 2。我们会的 确定AP-1和SMAD蛋白在前列腺癌细胞中的DMA结合活性 TGFP并确定C-Jun和Jun D在前列腺癌细胞增殖中的作用。 3。我们还将学习 TGFP对JUN家庭成员的JNK激活和磷酸化的影响并确定其 对细胞增殖的影响。我们将分析前列腺细胞中的C-Jun依赖基因表达 到TGFP以鉴定涉及细胞增殖抑制的下游信号传导成分。