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Functional analysis of a tumor suppressor candidate gene, HD-PTP, located on human chromosome 3p21

位于人类染色体3p21上的抑癌候选基因HD-PTP的功能分析

基本信息

批准号：
12670138
负责人：
OUCHIDA Mamoru
金额：
$ 2.11万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670138/
关键词：
Tumor suppressor Chromosome 3p21 Two-hybrid assay Yeast Two-hybrid 肺癌チロシンホスファターゼ Loss of Heterozygosity 遺伝子変異

项目摘要

A human HD-PTP cDNA encoding a novel protein tyrosine phosphatase has been isolated in our laboratory. The phosphatase has unique features in its domain structure : a Histidine-domain containing several SH3-binding motifs, a tyrosine phosphatase domain, a C-terminal PEST motif, and an N-terminal domain similar to yeast BRO1, an apoptpsis-related mammalian AIP1 and to a RHO-binding protein, Rhophilin. The gene is located at chromosome 3p21.3, an area frequently deleted in many types of cancer, especially within the functionally defined narrow region. The gene may be a human homolog of the rat PTP-TD14 gene reported by others, which can suppress H-ras- mediated transformation. The phosphatase gene may be a candidate for one of the tumor suppressor genes located on 3p21.3.To analyze the function of HD-PTP through the signal transduction, we screened new proteins, which can bind with each domain of HD-PTP, by yeast two-hybrid assay. As targets of BRO-domain, rabaptin 5, which is an effector of rab 5(GTPase protein), and HC8, which is proteosome alpha subunit and regulates the life time of cell cycle-related proteins, were isolated. It has been reported that tumor suppressor gene TSC2 product (tuberin) binds to rabaptin 5, suggesting that HD-PTP may be associated in the tumorigenesis through rabaptin 5/rab5 complex. As targets of Histidine-domain, DNA repair gene SOH1 was isolated. SOH1 is known to bind with the other repair enzymes and transcriptional factors, suggesting that HD-PTP may be associated with DNA repair system through transcription.

本实验室已分离到编码一种新的蛋白质酪氨酸磷酸酶的人HD-PTP基因。磷酸酶在结构域结构上有其独特的特征：一个含有几个SH3结合基序的组氨酸结构域，一个酪氨酸磷酸酶结构域，一个C-末端PEST基序，以及一个类似于酵母BRO1，一个与细胞凋亡相关的哺乳动物AIP1和一个Rho结合蛋白Rhophlin的N-末端结构域。该基因位于染色体3p21.3，这一区域在许多类型的癌症中经常缺失，特别是在功能定义的狭窄区域内。该基因可能是其他人报道的大鼠PTP-TD14基因的人类同源基因，可以抑制H-ras介导的转化。磷酸酶基因可能是位于3p21.3的肿瘤抑制基因之一。为了从信号转导的角度分析HD-PTP的功能，我们利用酵母双杂交技术筛选出能与HD-PTP的各个结构域结合的新蛋白。作为bro结构域的靶点，Rab 5(GTPase蛋白)的效应物Rabaptin 5和调节细胞周期相关蛋白生命时间的蛋白酶体α亚单位HC8被分离出来。已有报道肿瘤抑制基因TSC2产物(Tuberin)与Rabaptin 5结合，提示HD-PTP可能通过Rabaptin 5/rab5复合体参与肿瘤的发生。作为组氨酸结构域的靶点，克隆了DNA修复基因SOH1。已知的SOH1与其他修复酶和转录因子结合，提示HD-PTP可能通过转录与DNA修复系统相关。