VACM-1, cul 5 gene regulates cell growth & angiogenesis.

VACM-1、cul 5基因调节细胞生长

• 批准号: 6700971
• 负责人: MARIA BURNATOWSKA-HLEDIN
• 金额: $ 20.92万
• 依托单位: HOPE COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700971
• 关键词: SDS polyacrylamide gel electrophoresis; angiogenesis; biological signal transduction; calcium flux; cell proliferation; cyclic AMP; gene expression; genetic regulation; immunocytochemistry; intracellular; microarray technology; mitogen activated protein kinase; receptor; receptor binding; tissue /cell culture; vasopressins; western blottings

DESCRIPTION (provided by applicant): Although numerous growth factors and receptors, cytokines and chemokines, adhesion molecules, matrix proteins, proteases and transcription factors have been implicated in the formation of new blood vessels and in the tumor supported angiogenesis, the process is still not fully understood. We have cloned a novel, endothelium specific protein, VACM-1, which shares sequence homology with cullins, a family of intracellular proteins that regulate diverse cellular functions. Our work indicates that VACM-1 protein regulates cellular growth by a mechanism that distinguishes it from other growth regulating factors, and thus suggests a unique biological role for this largely uncharacterized cul gene product. The expression of VACM-1 mutant has a dominant negative effect on cellular proliferation in vitro and in the endothelial cells in vitro, increases cellular growth, and importantly converts these cells to the angiogenic phenotype. Consequently, VACM-1 may play a role as a potential novel suppressor of angiogenesis. Thus, the immediate goal of the research proposed here is to test the hypothesis that VACM-1 is involved in the regulation of endothelial cell growth and to identify the mechanism of VACM-1 regulated angiogenesis in vitro. Consequently, the work proposed in Aim 1 will elucidate the characteristics of the VACM-1 dominant negative phenotype in endothelial cells in vitro and thus will identify a novel factor that may be critical in the regulation of vascular growth. The studies proposed in Aim 2 will directly identify proteins that interact and/or are regulated by VACM-1 and thus establish the cellular mechanism of VACM-1 signaling pathway. The studies outlined in Aim 3 propose the use of antisense mRNA technology to confirm that the angiogenic phenotype induced by a VACM-1 mutant is indeed VACM-1 specific. These studies will provide us with a better understanding at the molecular and physiological level of VACM-1 dependent regulation of the endothelial cell growth and they will help to elucidate the mechanism of angiogenesis. Consequently, these results may lead to development of strategies for diagnosis and intervention in the pathologies of excessive vascularization and consequently cancer.

描述（由申请人提供）：尽管许多生长因子和受体，细胞因子和趋化因子，粘附分子，基质蛋白，蛋白酶和转录因子已与新血管的形成有关，并且在肿瘤支持的血管生成中涉及，但该过程仍未完全理解。 我们克隆了一种新颖的内皮特异性蛋白质Vacm-1，该蛋白质与Cullins共享序列同源性，Cullins是一个调节各种细胞功能的细胞内蛋白质。 我们的工作表明，VACM-1蛋白通过将其与其他调节因子区分开的机制调节细胞生长，因此暗示了这种很大程度上未表征的CUL基因产物的独特生物学作用。 VACM-1突变体的表达对体外和内皮细胞中细胞增殖具有显着负面影响，会增加细胞的生长，并重要地将这些细胞转化为血管生成表型。 因此，VACM-1可能是潜在的新型血管生成抑制剂。 因此，这里提出的研究的直接目标是检验以下假设：Vacm-1参与了内皮细胞生长的调节，并确定Vacm-1在体外调节血管生成的机制。 因此，在AIM 1中提出的工作将阐明体外内皮细胞中VACM-1显性阴性表型的特征，因此将确定一个新的因素，这可能对调节血管生长至关重要。 AIM 2中提出的研究将直接鉴定由VACM-1调节的蛋白质，从而建立VACM-1信号通路的细胞机理。 AIM 3中概述的研究提出使用反义mRNA技术来确认VACM-1突变体诱导的血管生成表型确实是Vacm-1特异性的。 这些研究将使我们在VACM-1的分子和生理水平上对内皮细胞生长的调节的分子和生理水平有更好的了解，它们将有助于阐明血管生成的机制。 因此，这些结果可能导致发展过度血管化和癌症的诊断和干预策略。

项目成果

CUL5 is required for thalidomide-dependent inhibition of cellular proliferation.

• DOI: 10.1371/journal.pone.0196760
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kunkler B;Salamango D;DeBruine ZJ;Ploch C;Dean S;Grossens D;Hledin MP;Marquez GA;Madden J;Schnell A;Short M;Burnatowska-Hledin MA
• 通讯作者: Burnatowska-Hledin MA