Epigenetic silencing of a Ca(2+)-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers.
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 GTPase-activating 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 Ca(2+)-regulated Ras GAP that decodes the frequency of Ca(2+) 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 Ca(2+) in the regulation of Ras signaling and has established that deregulation of this pathway is an important step in Ras-mediated tumorigenesis.
Jin
Hongchuan
H
State Key Laboratory in Oncology in South China, Sir Y. K. Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong.
Wang
Xian
X
Ying
Jianming
J
Wong
Ada H Y
AH
Cui
Yan
Y
Srivastava
Gopesh
G
Shen
Zhong-Ying
ZY
Li
En-Min
EM
Zhang
Qian
Q
Jin
Jie
J
Kupzig
Sabine
S
Chan
Anthony T C
AT
Cullen
Peter J
PJ
Tao
Qian
Q
D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D018899:CpG Islands; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008745:Methylation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D020703:ras GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D020703:ras GTPase-Activating Proteins; D018631:ras Proteins; D002118:Calcium