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Epigenetic silencing of a Ca2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers
Jin, Hongchuan; Wang, Xian; Ying, Jianming; Wong, Ada H. Y.; Cui, Yan; Srivastava, Gopesh; Shen, Zhong-Ying; Li, En-Min; Zhang, Qian; Jin, Jie; Kupzig, Sabine; Chan, Anthony T. C.; Cullen, Peter J.; Tao, Qian
关键词calcium Ras GTPase-activating-like protein tumorigenesis
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2007-07-24
DOI10.1073/pnas.0700153104
104期:30页:12353-12358
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Multidisciplinary Sciences
研究领域[WOS]Science & Technology - Other Topics
关键词[WOS]ABERRANT PROMOTER METHYLATION ; CANDIDATE TUMOR-SUPPRESSOR ; SQUAMOUS-CELL CARCINOMA ; STRESS-RESPONSIVE GENE ; PROSTATE-CANCER ; HDAB2IP GENE ; GAP1 FAMILY ; NASOPHARYNGEAL CARCINOMA ; EXPRESSION PROFILE ; BREAST-CANCER
英文摘要

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.

语种英语
WOS记录号WOS:000248472100023
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被引频次:75[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/63272
专题北京大学第一临床医学院_泌尿外科
作者单位1.Univ Bristol, Henry Wellcome Integrated Signalling Labs, Dept Biochem, Sch Med Sci, Bristol BS8 1TD, Avon, England
2.Chinese Univ Hong Kong, Canc Epigenet Lab, State Key Lab Oncol S China,Hong Kong Canc Inst, Sir YK Pao Ctr Canc,Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China
3.Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Si, Hong Kong, Hong Kong, Peoples R China
4.Peking Univ First Hosp, Dept Urol, Beijing, Peoples R China
5.Inst Urol, Beijing 100034, Peoples R China
6.Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China
7.Shantou Univ, Coll Med, Chinese Univ Hong Kong, Joint Epigenet Grp, Shantou 515041, Peoples R China
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Jin, Hongchuan,Wang, Xian,Ying, Jianming,et al. Epigenetic silencing of a Ca2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2007,104(30):12353-12358.
APA Jin, Hongchuan.,Wang, Xian.,Ying, Jianming.,Wong, Ada H. Y..,Cui, Yan.,...&Tao, Qian.(2007).Epigenetic silencing of a Ca2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,104(30),12353-12358.
MLA Jin, Hongchuan,et al."Epigenetic silencing of a Ca2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 104.30(2007):12353-12358.
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