Epigenetic silencing of a Ca 2+ -regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers
- 24 July 2007
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 104 (30), 12353-12358
- https://doi.org/10.1073/pnas.0700153104
Abstract
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 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.This publication has 57 references indexed in Scilit:
- Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphataseNature, 2006
- GAP1 Family Members Constitute Bifunctional Ras and Rap GTPase-activating ProteinsOnline Journal of Public Health Informatics, 2006
- Recent advances in Ca2+-dependent Ras regulation and cell proliferationCell Calcium, 2006
- Reversible intracellular translocation of KRas but not HRas in hippocampal neurons regulated by Ca2+/calmodulinThe Journal of cell biology, 2005
- A Genetic Screen for Candidate Tumor Suppressors Identifies RESTCell, 2005
- GAPs in growth factor signallingGrowth Factors, 2005
- Targeting RAS signalling pathways in cancer therapyNature Reviews Cancer, 2003
- GAP1IP4BP Contains a Novel Group I Pleckstrin Homology Domain That Directs Constitutive Plasma Membrane AssociationOnline Journal of Public Health Informatics, 2000
- Methylation Status of the Epstein-Barr Virus Major Latent Promoter C in Iatrogenic B Cell Lymphoproliferative Disease: Application of PCR-Based AnalysisThe American Journal of Pathology, 1999
- Nonsense mutations in the C–terminal SH2 region of the GTPase activating protein (GAP) gene in human tumoursNature Genetics, 1993