IDENTIFICATION OF TRANSFORMING GENES IN MELANOMA

1990年，近3万人患上了恶性黑色素瘤， 占美国所有新癌症病例的3%，6000人死亡 这种恶行。在过去的十年中，黑色素瘤的发病率 年增长速度快于除肺癌以外的任何其他癌症 女人。在美国，一个人的终生风险 恶性黑色素瘤在1987年为1：135，预计到2020年为1：90。 公元2000年。发病率增加的原因尚不清楚。 可以理解，但很可能与增加暴露在阳光下有关，增加 到达表面的紫外线辐射量，以及较早检测到的 黑色素瘤。 我们实验室最近的努力都是为了建造 并成功实现了一种cdna表达系统 人类恶性肿瘤中表达的活化癌基因的分离。 人黑色素瘤基因文库在NIH/3T3细胞中的表达克隆 发现了一个新的转化基因，命名为TIM-1 黑色素瘤。该基因没有与任何基因的全序列同源性。 基因库，然而，有一个102bp的区域，大约有30% 与位于基因DB1、BCR、CDC 24、ECT-2上的共同位点同源， CDC 25和Vav.这一同源性区域代表着一种不断扩大的 可能对生长控制很重要的基因家族。 探讨该基因在恶性肿瘤发病机制中的作用 对于黑色素瘤，我们提出了以下具体目标： 1.将转化的TIM-1基因导入永生化小鼠体内 黑素细胞及其对致瘤性的影响 #2.为了研究Tim-1基因在临床上可能起到的作用，我们将 筛选黑色素瘤标本、转移瘤和细胞系中的TIM-1基因 表情。还将检测TIM-1在正常人中的表达 组织和发育中的小鼠体内。 #3.将分离全长TIM-1基因(6.8kb)，并将其 转化活性，相对于克隆的转化cDNA(2.4kb)， 将会被检查。 #4.定义TIM-1基因的染色体定位并表征 TIM-1蛋白。

In 1990 nearly 30,000 individuals developed malignant melanoma, representing 3% of all new cancer cases in the U.S. and 6000 people died of this malignancy. In the past decade, the incidence of melanoma increased faster than that of any other cancer except lung cancer in women. The lifetime risks of an individual in the U.S. developing malignant melanoma was 1:135 in 1987 and is projected to be 1:90 by the year 2000. The reasons for the increased incidence are not clearly understood but likely relate to increased exposure to sunlight, increased amount of Uv irradiation reaching the surface, and earlier detection of melanomas. Recent efforts in our laboratory have been directed to the construction and implementation of a cDNA expression system that has been successful in the isolation of activated oncogenes expressed in human malignancies. Expression cloning of a human melanoma cDNA library into NIH/3T3 cells has identified a novel transforming gene, termed tim-1, for transforming in melanoma. This gene has no overall sequence homology to any genes in Genebank, however there is a 102 bp region that is approximately 30% homologous to a common site located on the genes dbl, bcr, CDC 24, ect-2, CDC 25, and vav. This region of homology is representive of an expanding family of genes which may be important to growth control. To investigate the role this gene has in the pathogenesis of malignant melanoma, we propose the following specific aims: #1. We will transfect the transforming tim-1 cDNA into immortalized mouse melanocytes and determine its effect on tumorigenicity #2. To investigate the role the tim-1 gene may have clinically, we will screen melanoma specimens, metastases, and cell lines for tim-1 gene expression. The expression of tim-1 will also be examined in normal human tissue and in the developing mouse. #3. The full-length tim-1 cDNA (6.8 kb) will be isolated and its transforming activity, relative to the cloned transforming cDNA (2.4 kb), will be examined. #4. Define the chromosomal localization of the tim-1 gene and characterize the tim-1 protein.