Premium
Role of the Rap1 GTPase in astrocyte growth regulation
Author(s) -
Apicelli Anthony J.,
Uhlmann Erik J.,
Baldwin Rebecca L.,
Ding Hao,
Nagy Andras,
Guha Abhijit,
Gutmann David H.
Publication year - 2003
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.10214
Subject(s) - astrocyte , rap1 , biology , transgene , tsc2 , small gtpase , genetically modified mouse , cancer research , endocrinology , microbiology and biotechnology , medicine , signal transduction , genetics , pi3k/akt/mtor pathway , gene , central nervous system
Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which affected individuals develop nervous system abnormalities that might reflect astrocyte dysfunction. The TSC2 gene product, tuberin, encodes a GTPase‐activating protein (GAP) domain, which regulates the activity of Rap1 in vitro. To determine whether dysregulated Rap1, resulting from TSC2 inactivation, leads to increased astrocyte proliferation in vivo, we generated transgenic mice expressing activated Rap1 G12V specifically in astrocytes. We observed no statistically significant difference in the number of astrocytes between wild‐type and GFAP‐Rap1 G12V littermates in vivo; however, during log‐phase growth, we observed a 25% increase in GFAP‐Rap1 G12V astrocyte doubling times compared to wild‐type controls. This decreased proliferation was associated with delayed MAP kinase, but not AKT, activation. Lastly, to determine whether constitutive Rap1 activation could reverse the increased astrocyte proliferation observed in transgenic mice expressing oncogenic Ras G12V , we generated transgenic mice expressing both Ras G12V and Rap1 G12V in astrocytes. These double transgenic mice showed a striking reversion of the Ras G12V astrocyte growth phenotype. Collectively, these results argue that the tumor suppressor properties of tuberin are unlikely to be related to Rap1 inactivation and that Rap1 inhibits mitogenic Ras pathway signaling in astrocytes. GLIA 42:225–234, 2003. © 2003 Wiley‐Liss, Inc.