Johnstone Cameron N, Castellví-Bel Sergi, Chang Laura M, Bessa Xavier, Nakagawa Hiroshi, Harada Hideki, Sung Raphael K, Piqué Josep M, Castells Antoni, Rustgi Anil K
Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadellphia, PA 19104, USA.
Gene. 2004 Jul 7;336(1):59-71. doi: 10.1016/j.gene.2004.01.025.
The RHO family of small GTPases has multiple functions, including regulation of cytoskeletal organization, cell cycle progression and cell migration, among others. The key members of this family are RHO, RAC and CDC42. Active GTP-bound RHO proteins are down-regulated by RHO GTPase-activating proteins (RHOGAPs). Herein, we describe the identification, characterization and mutational analysis of a novel RHOGAP designated as ARHGAP8, which is located within a critical region of loss-of-heterozygosity on chromosome 22q13.31 in breast and colorectal carcinomas. ARHGAP8 shares an identical genomic organization with ARHGAP1/CDC42GAP/p50RHOGAP and the corresponding proteins share the same functional domains that distinguish them from other ARHGAP members. These domains include the C-terminal RHOGAP domain, a central SH3-binding motif, and an N-terminal BNIP-2/CDC42GAP homology (BCH)/Sec14p-like domain. Three alternatively spliced ARHGAP8 transcripts were expressed in normal mammary gland and colon, which differed in the size of the BCH/Sec14p-like domain only. PCR-SSCP analyses revealed a total of six germline missense variants in individuals with colorectal or breast cancer; however, somatic mutations were not identified. Surprisingly, ARHGAP8 expression was up-regulated in the majority of primary colorectal tumors analyzed. Taken together, ARHGAP8 encodes a novel RHOGAP with unique functional domains that is highly homologous to ARHGAP1/CDC42GAP/p50RHOGAP.
小GTP酶的RHO家族具有多种功能，包括调节细胞骨架组织、细胞周期进程和细胞迁移等。该家族的关键成员是RHO、RAC和CDC42。活性GTP结合的RHO蛋白受RHO GTP酶激活蛋白（RHOGAPs）负调控。在此，我们描述了一种新型RHOGAP（命名为ARHGAP8）的鉴定、特征及突变分析，其位于乳腺癌和结直肠癌22q13.31染色体杂合性缺失的关键区域。ARHGAP8与ARHGAP1/CDC42GAP/p50RHOGAP具有相同的基因组结构，相应蛋白具有相同的功能结构域，使其区别于其他ARHGAP成员。这些结构域包括C端RHOGAP结构域、中央SH3结合基序以及N端BNIP-2/CDC42GAP同源（BCH）/Sec14p样结构域。三种可变剪接的ARHGAP8转录本在正常乳腺和结肠中表达，仅在BCH/Sec14p样结构域大小上有所不同。PCR-SSCP分析揭示，结直肠癌或乳腺癌患者共有6种种系错义变异；然而，未发现体细胞突变。令人惊讶的是，在大多数分析的原发性结直肠癌肿瘤中，ARHGAP8表达上调。综上所述，ARHGAP8编码一种具有独特功能结构域的新型RHOGAP，与ARHGAP1/CDC42GAP/p50RHOGAP高度同源。
