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

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负责细胞生长，分化和肿瘤转化的分子和遗传机制。我们研究的癌基因，肿瘤抑制基因和信号转导蛋白参与BALB/c小鼠浆细胞瘤，B细胞淋巴瘤和其他小鼠和人类实验肿瘤系统。这些都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设计更具体的治疗和预防措施。BALB/c浆细胞瘤，像人伯基特淋巴瘤，其特征在于组成型表达的信使RNA和蛋白质的主癌基因，c-Myc。目前还不清楚需要哪些额外的遗传改变才能完成转化。我们正在使用微阵列杂交研究全球基因表达的变化，在基因表达duting从癌前病变到完全恶性浆细胞肿瘤的进展。在信号转导的研究中，我们正在调查蛋白激酶C（PKC），一个多基因家族的丝氨酸/苏氨酸激酶，是许多形式的信号转导的重要介质的异构体的具体特点。我们一直专注于δ和β同工酶，这对细胞增殖有相反的影响。我们已经证明，大多数同工酶特异性决定簇位于催化的一半（羧基末端结构域），这些蛋白激酶通过创建相互嵌合的cDNA编码的分子，是半PKC-δ和半PKC-β。我们正在进一步解剖催化结构域的结构，以确定哪些亚结构域决定PKC亚型的特异性功能，重点是羧基末端的50个氨基酸，即“V5结构域”。“我们还在研究PKC参与细胞凋亡、细胞形态和运动性的细胞凋亡相关变化以及这些和其他类型肿瘤（包括人前列腺癌）转移的性质。我们已经表明，佛波酯激活过表达的PKC-δ破坏了人类和小鼠淋巴细胞中的肌动蛋白细胞骨架，导致膜皱褶的丧失，细胞运动所需的表面改变，以及这些细胞典型的细长形状的丧失。我们认为这种效应是由于PKC介导的衔接分子桩蛋白磷酸化的变化。