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

人类HD-PTP cDNA编码一种新的蛋白酪氨酸磷酸酶已分离在我们的实验室。该磷酸酶在结构域结构上具有独特的特征：一个包含多个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端PEST结构域和一个类似于酵母BRO1、与凋亡相关的哺乳动物AIP1和rho结合蛋白Rhophilin的n端结构域。该基因位于染色体3p21.3，该区域在许多类型的癌症中经常被删除，特别是在功能定义的狭窄区域内。该基因可能是其他报道的大鼠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的候选基因。为了通过信号转导分析HD-PTP的功能，我们通过酵母双杂交实验筛选了能够与HD-PTP各结构域结合的新蛋白。作为BRO-domain的靶点，分离出了rabaptin 5（GTPase蛋白）的效应因子和HC8（蛋白体α亚基，调控细胞周期相关蛋白的寿命）。据报道，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复合物参与肿瘤发生。作为组氨酸结构域的靶点，DNA修复基因SOH1被分离出来。已知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。

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.