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Article: Epigenetic silencing of a Ca 2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers

TitleEpigenetic silencing of a Ca 2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers
Authors
Issue Date2007
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings of the National Academy of Sciences, 2007, v. 104 n. 30, p. 12353-12358 How to Cite?
AbstractRas 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. © 2007 by The National Academy of Sciences of the USA.
Persistent Identifierhttp://hdl.handle.net/10722/148518
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorJin, Hen_US
dc.contributor.authorWang, Xen_US
dc.contributor.authorYing, Jen_US
dc.contributor.authorWong, AHYen_US
dc.contributor.authorCui, Yen_US
dc.contributor.authorSrivastava, Gen_US
dc.contributor.authorShen, ZYen_US
dc.contributor.authorLi, EMen_US
dc.contributor.authorZhang, Qen_US
dc.contributor.authorJin, Jen_US
dc.contributor.authorKupzig, Sen_US
dc.contributor.authorChan, ATCen_US
dc.contributor.authorCullen, PJen_US
dc.contributor.authorTao, Qen_US
dc.date.accessioned2012-05-29T06:13:27Z-
dc.date.available2012-05-29T06:13:27Z-
dc.date.issued2007en_US
dc.identifier.citationProceedings of the National Academy of Sciences, 2007, v. 104 n. 30, p. 12353-12358en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://hdl.handle.net/10722/148518-
dc.description.abstractRas 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. © 2007 by The National Academy of Sciences of the USA.en_US
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.-
dc.subject.meshCalcium - Metabolismen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshChromosomes, Human, Pair 12 - Geneticsen_US
dc.subject.meshCpg Islandsen_US
dc.subject.meshDown-Regulationen_US
dc.subject.meshEnzyme Activationen_US
dc.subject.meshGene Expression Regulation, Neoplasticen_US
dc.subject.meshGene Silencingen_US
dc.subject.meshHumansen_US
dc.subject.meshMethylationen_US
dc.subject.meshNeoplasms - Genetics - Metabolism - Pathologyen_US
dc.subject.meshPhenotypeen_US
dc.subject.meshRas Gtpase-Activating Proteins - Genetics - Metabolismen_US
dc.subject.meshRas Proteins - Metabolismen_US
dc.titleEpigenetic silencing of a Ca 2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancersen_US
dc.typeArticleen_US
dc.identifier.emailSrivastava, G: gopesh@pathology.hku.hken_US
dc.identifier.authoritySrivastava, G=rp00365en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1073/pnas.0700153104en_US
dc.identifier.pmid17640920en_US
dc.identifier.pmcidPMC1941473-
dc.identifier.scopuseid_2-s2.0-34547619642en_US
dc.identifier.hkuros132741-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34547619642&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume104en_US
dc.identifier.issue30en_US
dc.identifier.spage12353en_US
dc.identifier.epage12358en_US
dc.identifier.isiWOS:000248472100023-
dc.publisher.placeUnited Statesen_US
dc.customcontrol.immutablesml 130621-

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