MELANOMA CELL SURFACE PROTEOGLYCANS IN METASTASIS

性状：（改编自研究者摘要）黑色素瘤软骨素 硫酸化蛋白聚糖（MCSP），也称为高分子量黑素瘤 相关抗原（HMW-MAA）是一种大的、高抗原性的细胞表面抗原 在黑色素瘤中显著上调的蛋白聚糖。MCSP正在 作为黑色素瘤疫苗开发的靶点， 限制性表达和抗原特性。尽管其潜在的临床 重要的是，对MCSP在黑素瘤中的作用知之甚少 进展先前的研究表明MCSP与粘附、运动或细胞增殖有关。 细胞生长控制。他提供的数据表明， 通过反义寡核苷酸表达MCSP抑制肿瘤侵袭， 在软琼脂中体外生长。他已经证明，小额信贷社区支助方案的职能是 粘附分子，部分通过增强a4 b1整合素， 介导肿瘤侵袭和抑制。此外，他还发现了一本小说 MCSP刺激的信号通路。MCSP的激活导致快速的 衔接蛋白p130 cas的结合和酪氨酸磷酸化 与肿瘤运动和侵袭有关。这一信号通路还涉及 MCSP与cdc 42（一种rho家族GT3， 丝状伪足形成、细胞运动和生长。此外，Ack-1，一种酪氨酸激酶， 与活性（即，GTP结合）cdc 42， MCSP诱导p130 cas酪氨酸磷酸化。数据汇总如下： 这与MCSP通过以下方式增强肿瘤生长和侵袭的模型一致： 响应于信号传导复合物的信号传导， 外部刺激在本申请中，他将进一步定义该信令 研究其对黑色素瘤生长、侵袭和转移的重要性。 此外，虽然MCSP序列已公布，但它以前没有 被克隆了他最近扩增了MCSP的全长编码序列 通过RT-PCR的人黑色素瘤mRNA，并在表达过程中， 转染的黑色素瘤细胞缺乏MCSP。这个克隆体将使他们能够 审查MCSP、其 细胞外刺激及其细胞内信号转导。他提议 三个具体目标：1.为了评估MCSP表达的重要性， 在恶性黑色素瘤细胞的生长、侵袭和转移中起作用。2. 阐明Ack-1在MCSP诱导的酪氨酸磷酸化中的作用机制。 p130 cas的表达，并研究其在肿瘤的生存、生长和转移中的作用机制。 恶性黑色素瘤细胞3.确定小额信贷社区支助方案核心的职能领域 信号传导和黑色素瘤生长、侵袭和转移所需的蛋白质。

DESCRIPTION: (Adapted from the investigator's abstract) Melanoma chondroitin sulfate proteoglycan (MCSP), also known as high molecular weight melanoma associated antigen (HMW-MAA) is large, highly antigenic cell surface proteoglycan that is dramatically upregulated in melanoma. MCSP is being actively pursued as a target for melanoma vaccine development due to its restricted expression and antigenic properties. Despite its potential clinical importance, relatively little is known about the role of MCSP in melanoma progression. Previous studies have implicated MCSP in adhesion, motility, or cellular growth control. He presents data to demonstrate that inhibition of MCSP expression by anti-sense oligonucleotides inhibits tumor invasion and growth in soft agar in vitro. He has demonstrated that MCSP functions as an adhesion molecule, in part by enhancing the activity of a4b1 integrin, a mediator of tumor invasion and arrest. In addition, he has identified a novel signaling pathway stimulated by MCSP. Activation of MCSP leads to the rapid association and tyrosine phosphorylation of p130cas, an adapter protein implicated in tumor motility and invasion. This signaling pathway also involves the association of MCSP with cdc42, a rho-family GTPase that mediates filopodial formation, cell motility and growth. Furthermore, Ack-1, a tyrosine kinase that associates with active (i.e., GTP bound) cdc42, is required for MCSP induced tyrosine phosphorylation of p130cas. Collectively the data are consistent with a model in which MCSP enhances tumor growth and invasion by sequestering intracellular components of a signaling complex in response to an external stimulus. In this application he will further define that signaling complex and study its importance for melanoma growth, invasion and metastasis. Additionally, although the MCSP sequence is published, it has not previously been cloned. He has recently amplified the full-length coding sequence for MCSP by RT-PCR of human melanoma mRNA and are in the process of expressing it in transfected melanoma cells which lack MCSP. This clone will enable them to examine the structural and functional relationships between MCSP, its extracellular stimuli, and its intracellular signal transduction. He proposes three specific aims: 1. To evaluate the importance of MCSP expression and function in the growth, invasion and metastasis of malignant melanoma cells. 2. To delineate the mechanism of Ack-1 in MCSP induced tyrosine phosphorylation of p130cas and to study this mechanism in the survival, growth and metastasis of malignant melanoma cells. 3. To define functional domains of the MCSP core protein required for signaling and melanoma growth, invasion and metastasis.