Expression/Signal Transduction-Transformation/Different.

我们的研究目标是了解细胞生长、分化和肿瘤转化的分子和遗传机制。我们研究了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的癌基因、肿瘤抑制基因和信号转导蛋白。这些是有价值的实验模型，因为它们可以用于设计更具体的治疗和预防措施，用于人类多发性骨髓瘤、非霍奇金淋巴瘤和其他人类恶性肿瘤。与人类伯基特淋巴瘤一样，BALB/c浆细胞瘤的特征是主要致癌基因c- myc的信使RNA和蛋白质的组成性表达。目前还不清楚，完全转化需要哪些额外的基因改变。我们正在使用微阵列杂交技术研究全球基因表达，以跟踪从癌前到完全恶性浆细胞肿瘤进展过程中基因表达的变化。在信号转导的研究中，我们正在研究蛋白激酶C （PKC）的异构体特异性特征，PKC是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。我们一直在关注δ和ε同工酶，它们对细胞增殖有相反的作用。我们已经证明，大多数同工酶特异性决定因子位于这些PKCs的催化一半（羧基末端结构域），通过创建互惠嵌合cdna编码一半PKC-delta和一半PKC-epsilon的分子。我们正在进一步剖析催化结构域的结构，以确定哪些子结构域决定PKC异构体特异性功能，重点关注羧基末端50个氨基酸，即“V5结构域”。我们也在研究PKC参与细胞凋亡、细胞骨架相关的细胞形状和运动变化以及这些和其他类型肿瘤（包括人类前列腺癌）转移的本质。我们已经证明，磷酸化酯激活过表达的pkc - δ会破坏人和小鼠淋巴细胞中的肌动蛋白细胞骨架，导致细胞膜褶皱（细胞运动所需的表面改变）的丧失，以及这些细胞典型的细长形状的丧失。我们认为这种作用是由于pkc介导的接头分子paxillin磷酸化的变化。

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.