• high grade glioma

This Drosophila model of malignant glioma uses the GAL4/UAS system to drive expression of an activated form of Dmel\Ras85D (the allele Ras85D^V12) and an RNAi knockdown construct of Dmel\Pten in glial cells. The resulting animals exhibit larval glial neoplasms in the brain. The role of downstream genes and their contributions to tumorigenic phenotypes have been assessed.

The human PTEN (phosphatase and tensin homolog, MIM:601728) gene was originally identified as a tumor suppressor gene; it is mutated at a high frequency in multiple cancers, especially at advanced stages. PTEN acts as a dual-specificity phosphatase that functions as a tumor suppressor by negatively regulating the PI3K-AKT/PKB signaling pathway. Multiple UAS constructs of Hsap\PTEN have been introduced into flies, but have not been characterized in the context of this disease model.

There is a single gene orthologous to PTEN in Drosophila, Dmel\Pten, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Animals homozygous for loss-of-function mutations of Pten are substantially increased in size compared to controls; increase in size is also observed for somatic clones and for tissues subject to targeted loss of function. An extensive number of physical and genetic interactions of Dmel\Pten have been described; see below and in the Pten gene report.

The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers and are crucial players in many signaling networks affecting cell cycle progression, growth, migration, cytoskeletal changes, apoptosis, and senescence. Originally defined as oncogenes, the RAS GTPase family includes KRAS (MIM:190070), HRAS (MIM:190020), and NRAS (MIM:164790); mutations in these three genes are among the most common events in human cancers. For KRAS, HRAS and NRAS, there is a single high-scoring ortholog in Drosophila, Ras85D, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. There are multiple other paralogous and orthologous genes in both species. Of the three human RAS GTPase genes, a tagged UAS construct of Hsap\HRAS has been introduced into flies, but has not been characterized.

The constitutively active Ras85D mutation, Ras85D^V12, is analogous to oncogenic mutations found in human RAS proteins. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G12V in the fly Ras85D gene (corresponds to G12V in the human KRAS and HRAS genes). See also the human disease model reports 'cancer, multiple, RAS-related'.

Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. Most work relevant to cancer has been done with an activated form of the gene, Ras85D^V12. This allele is usually lethal during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85D^V12 exhibit an overgrowth phenotype in multiple different tissues tested. Many physical and genetic interactions for Dmel\Ras85D have been described; see below and in the gene report for Ras85D.

See also the human disease model reports 'cancer, multiple, RAS-related' (FBhh0000474), lung cancer, RAS-PTEN-related (FBhh0000657), and cancer, multiple, PIK3C-related (FBhh0000400).

[updated Nov. 2018 by FlyBase; FBrf0222196]