Epigenetic silencing of a Ca2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers
Epigenetic silencing of a Ca2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers
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DOI：
10.1073/pnas.0700153104
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发表时间：
2007-07-24
影响因子：
11.1
通讯作者：
Tao, Qian
中科院分区：
文献类型：
--
作者：
Jin, Hongchuan;Wang, Xian;Tao, Qian
Ras作为一种在多种人类肿瘤中异常激活的癌基因而声名狼借。大约30%的人类肿瘤表达这种GTP酶的致癌形式，由于对Ras GTP酶激活蛋白（GAP）不敏感，这种GTP酶被锁定在活性构象中，这些蛋白通常通过增强其内在的GTP酶活性来调节Ras的失活。除了Ras中的致癌突变之外，野生型Ras的信号传导也经常通过与活化的细胞表面受体的异常偶联而在肿瘤中失调。这表明异常野生型Ras激活的替代机制可能参与肿瘤发生。在这里，我们描述了另一种机制，通过这种机制，异常Ras激活在人类癌症中实现。我们已经确定，Ras GTP酶激活样蛋白（RASAL），一种Ca2+调节的Ras GAP，解码Ca2+振荡的频率，在多种肿瘤中通过CpG甲基化沉默。随着催化活性RASAL的异位表达通过Ras失活导致这些肿瘤细胞的生长抑制的发现，我们提供了证据，该Ras GAP的表观遗传学沉默代表某些癌症中异常Ras活化的机制。因此，我们证明RASAL是一种肿瘤抑制基因，进一步强调了Ca 2+在Ras信号调节中的重要性，并确定了该途径的失调是Ras介导的肿瘤发生的重要步骤。
Ras has achieved notoriety as an oncogene aberrantly activated in multiple human tumors. Approximately 30% of all human tumors express an oncogenic form of this GTPase that is locked in an active conformation as a result of being insensitive to Ras GTPaseactivating proteins (GAPs), proteins that normally regulate the inactivation of Ras by enhancing its intrinsic GTPase activity. Besides oncogenic mutations in Ras, signaling by wild-type Ras is also frequently deregulated in tumors through aberrant coupling to activated cell surface receptors. This indicates that alternative mechanisms of aberrant wild-type Ras activation may be involved in tumorigenesis. Here, we describe another mechanism through which aberrant Ras activation is achieved in human cancers. We have established that Ras GTPase-activating-like protein (RASAL), a Ca2+-regulated Ras GAP that decodes the frequency of Ca2+ oscillations, is silenced through CpG methylation in multiple tumors. With the finding that ectopic expression of catalytically active RASAL leads to growth inhibition of these tumor cells by Ras inactivation, we have provided evidence that epigenetically silencing of this Ras GAP represents a mechanism of aberrant Ras activation in certain cancers. Our demonstration that RASAL constitutes a tumor suppressor gene has therefore further emphasized the importance of Ca2+ in the regulation of Ras signaling and has established that deregulation of this pathway is an important step in Ras-mediated tumorigenesis.