Expression/Signal Transduction-Transformation/Different.

表达/信号转导-转化/不同。

• 批准号: 7048235
• 负责人: J F MUSHINSKI
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/7048235
• 关键词: biological signal transduction; cell differentiation; cell growth regulation; cell morphology; cell proliferation; chromosome translocation; enzyme activity; gene expression; gene expression profiling; genetic regulation; isozymes; laboratory mouse; microarray technology; neoplasm /cancer genetics; neoplastic transformation; oncogenes; paxillin; plasma cell neoplasm; prostate neoplasms; protein kinase C; protein structure function; transfection; tumor suppressor genes; biological signal transduction; cell differentiation; cell growth regulation; cell morphology; cell proliferation; chromosome translocation; enzyme activity; gene expression; gene expression profiling; genetic regulation; isozymes; laboratory mouse; microarray technology; neoplasm /cancer genetics; neoplastic transformation; oncogenes; paxillin; plasma cell neoplasm; prostate neoplasms; protein kinase C; protein structure function; transfection; tumor suppressor genes

Our research objective is to understand the molecular and genetic mechanisms responsible for cell growth, differentiation and neoplastic transformation. We study the oncogenes, tumor-suppressor genes and signal-transducing proteins involved in BALB/c mouse plasmacytomas, B-cell lymphomas and other mouse and human experimental tumor systems. These are valuable experimental models, because they can be used to devise more specific therapy and preventive measures for human multiple myeloma, non-Hodgkin's lymphomas, and other human malignancies. BALB/c plasmacytomas, like human Burkitt lymphomas, are characterized by constitutive expression of messenger RNA and protein from the master oncogene, c-Myc. It is still not clear which additional genetic alterations are required for complete transformation. We are using microarray hybridization studies of global gene expression to follow changes in gene expression duting progression from premalignant to fully malignant plasma cell tumors.In the study of signal transduction, we are investigating the isoform-specific features of protein kinase C (PKC), a multigene family of serine/threonine kinases that are important mediators of many forms of signal transduction. We have been focusing on the delta and epsilon isoenzymes, which have opposing effects on cell proliferation. We have shown that most of the isoenzyme-specific determinants are located in the catalytic half (the carboxyl-terminal domain) of these PKCs by creating reciprocal chimeric cDNAs that encode molecules that are half PKC-delta and half PKC-epsilon. We are further dissecting the structure of the catalytic domain to determine which sub-domains determine PKC isoform- specific functions, focusing on the carboxy-terminal 50 amino acids, the "V5 domain." We are also studying the nature of PKC's involvement in apoptosis, in cytoskeleton-related changes in cell shape and motility, and in metastasis of these and other types of tumors, including human prostate cancer. We have shown that phorbol ester-activation of overexpressed PKC-delta disrupts the actin cytoskeleton in human and mouse lymphocytes, leading to the loss of membrane ruffling, a surface alteration needed for cell movement, and the loss of the typical elongated shape of these cells. We think that this effect is due to PKC-mediated changes in the phosphorylation of the adaptor molecule, paxillin.

我们的研究目标是了解导致细胞生长，分化和肿瘤转化的分子和遗传机制。我们研究了涉及BALB/C小鼠浆细胞瘤，B细胞淋巴瘤以及其他小鼠和人类实验性肿瘤系统的肿瘤基因，肿瘤抑制基因和信号转推蛋白。这些是有价值的实验模型，因为它们可用于为人类多发性骨髓瘤，非霍奇金淋巴瘤和其他人类恶性肿瘤制定更具体的疗法和预防措施。 BALB/C浆细胞瘤（如人伯基特淋巴瘤）的特征在于主体RNA和蛋白质的构成表达，蛋白质是从癌基因c-myc的蛋白质。目前尚不清楚完全转化需要哪些其他遗传改变。我们正在使用对全球基因表达的微阵列杂交研究研究，以遵循基因表达的变化，从前态度到完全恶性血浆血浆细胞肿瘤的进展。在信号转导的研究中，我们正在研究蛋白激酶C（PKC）的同种特异性特异性特异性特异性特异性特异性特异性，这些特征是丝氨酸/硫氨酸酶的多种信号酶迁移的多形式的杂物酶的多种信号酶。我们一直专注于三角洲和埃普西隆同工酶，它们对细胞增殖有相反的影响。我们已经表明，大多数同工酶特异性决定因素位于这些PKC的催化半（羧基末端结构域）中，通过创建编码半pkc-delta和一半pkc-epsilon的相互嵌合cDNA。我们正在进一步剖析催化结构域的结构，以确定哪些子域确定PKC同工型 - 特异性功能，重点是羧基末端50氨基酸，即“ V5结构域”。我们还研究了PKC参与细胞凋亡的性质，细胞骨架相关的细胞形状和运动性变化以及这些和其他类型的肿瘤的转移，包括人类前列腺癌。我们已经表明，过表达PKC-DELTA的佛波酯激活破坏了人和小鼠淋巴细胞中肌动蛋白的细胞骨架，导致膜皱纹的丧失，细胞运动所需的表面改变以及这些细胞典型的细胞形状的丧失。我们认为这种作用是由于PKC介导的衔接子分子Paxillin的磷酸化变化所致。