Dammann R, Schagdarsurengin U, Strunnikova M, Rastetter M, Seidel C, Liu L, Tommasi S, Pfeifer G P
AG Tumorgenetik der Medizinischen Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
Histol Histopathol. 2003 Apr;18(2):665-77. doi: 10.14670/HH-18.665.
The Ras GTPases are a superfamily of molecular switches that regulate cellular proliferation and apoptosis in response to extra-cellular signals. The regulation of these pathways depends on the interaction of the GTPases with specific effectors. Recently, we have cloned and characterized a novel gene encoding a putative Ras effector: the Ras-association domain family 1 (RASSF1) gene. The RASSF1 gene is located in the chromosomal segment of 3p21.3. The high allelic loss in a variety of cancers suggested a crucial role of this region in tumorigenesis. At least two forms of RASSF1 are present in normal human cells. The RASSF1A isoform is highly epigenetically inactivated in lung, breast, ovarian, kidney, prostate, thyroid and several other carcinomas. Re-expression of RASSF1A reduced the growth of human cancer cells supporting a role for RASSF1 as a tumor suppressor gene. RASSF1A inactivation and K-ras activation are mutually exclusive events in the development of certain carcinomas. This observation could further pinpoint the function of RASSF1A as a negative effector of Ras in a pro-apoptotic signaling pathway. In malignant mesothelioma and gastric cancer RASSF1A methylation is associated with virus infection of SV40 and EBV, respectively, and suggests a causal relationship between viral infection and progressive RASSF1A methylation in carcinogenesis. Furthermore, a significant correlation between RASSF1A methylation and impaired lung cancer patient survival was reported, and RASSF1A silencing was correlated with several parameters of poor prognosis and advanced tumor stage (e.g. poor differentiation, aggressiveness, and invasion). Thus, RASSF1A methylation could serve as a useful marker for the prognosis of cancer patients and could become important in early detection of cancer.
Ras GTP酶是一类分子开关超家族，可响应细胞外信号调节细胞增殖和凋亡。这些信号通路的调节取决于GTP酶与特定效应器的相互作用。最近，我们克隆并鉴定了一个编码假定Ras效应器的新基因：Ras关联结构域家族1（RASSF1）基因。RASSF1基因位于3p21.3染色体区段。多种癌症中该区域的高频率等位基因缺失表明其在肿瘤发生中起关键作用。正常人类细胞中至少存在两种形式的RASSF1。RASSF1A异构体在肺癌、乳腺癌、卵巢癌、肾癌、前列腺癌、甲状腺癌和其他几种癌症中高度表观遗传失活。RASSF1A的重新表达降低了人类癌细胞的生长，支持RASSF1作为肿瘤抑制基因的作用。在某些癌症的发生过程中，RASSF1A失活和K-ras激活是相互排斥的事件。这一观察结果可进一步明确RASSF1A作为Ras在促凋亡信号通路中的负效应器的功能。在恶性间皮瘤和胃癌中，RASSF1A甲基化分别与SV40和EBV病毒感染相关，提示病毒感染与致癌过程中RASSF1A的渐进性甲基化之间存在因果关系。此外，有报道称RASSF1A甲基化与肺癌患者生存率受损之间存在显著相关性，RASSF1A沉默与预后不良和肿瘤晚期的几个参数相关（如低分化、侵袭性和浸润）。因此，RASSF1A甲基化可作为癌症患者预后的有用标志物，在癌症早期检测中可能变得重要。
