• cancer

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.

UAS constructs of Hsap\KRAS and Hsap\HRAS have been introduced into flies. Experiments with the KRAS G12D variant include assessments of pharmaceutical candidates. Variant(s) implicated in human disease tested (as transgenic human gene, KRAS): the G12D variant form of KRAS has been introduced into flies; this variant in implicated in multiple cancers. The Hsap\HRAS gene has been studied in a fly model of Costello syndrome (FBhh0001345).

The constitutively active Ras85D mutation, Ras85D^V12, is analogous to one of the most common 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, HRAS and NRAS genes).

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. Cell lines with Ras85D^V12-GFP (eg., Ras[V12]-H3, FBtc0000200) have been used to create oncogenic cells that can be injected into adult flies and the subsequent response monitored.

The Ras85D^V12 activated mutation produces overproliferation phenotypes, but typically does not result in phenotypes indicative of metastasis (or results in a low frequency of these phenotypes). A number of Drosophila models of multigenic cancers combine activated Ras85D with other genes known or suspected to contribute to the development and progression of cancer. See the 'Related Diseases' section, below, for a listing and links to these disease model reports.

[updated Nov. 2021 by FlyBase; FBrf0222196]