Role of the Rap1 GTPase in astrocyte growth regulation

• Published in: Glia 2003-05, Vol.42 (3), p.225-234
• Main Authors: Apicelli, Anthony J., Uhlmann, Erik J., Baldwin, Rebecca L., Ding, Hao, Nagy, Andras, Guha, Abhijit, Gutmann, David H.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Astrocytes - enzymology; astrocytoma; Biological and medical sciences; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Division - physiology; Cells, Cultured; Central Nervous System - enzymology; Central Nervous System - growth & development; Central Nervous System - physiopathology; Cyclin-Dependent Kinase Inhibitor p27; Down-Regulation - genetics; glia; glioma; MAP Kinase Signaling System - genetics; MAPK; Medical sciences; Mice; Mice, Transgenic; Neurology; Protein Structure, Tertiary - genetics; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; rap1 GTP-Binding Proteins - metabolism; RAS; ras Proteins - genetics; ras Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Tuberous Sclerosis - enzymology; Tuberous Sclerosis - genetics; Tuberous Sclerosis - physiopathology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors of the nervous system. Phacomatoses
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.10214

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 Rap1G12V specifically in astrocytes. We observed no statistically significant difference in the number of astrocytes between wild‐type and GFAP‐Rap1G12V littermates in vivo; however, during log‐phase growth, we observed a 25% increase in GFAP‐Rap1G12V 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 RasG12V, we generated transgenic mice expressing both RasG12V and Rap1G12V in astrocytes. These double transgenic mice showed a striking reversion of the RasG12V 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.