• cancer

This report describes a Drosophila model of cancer that combines an activated mutation in the fly RAS protein Ras85D with a loss-of-function mutation in the fly gene orthologous to the human CSK kinase gene. Phosphorylation by CSK suppresses the activity of multiple genes, including the SRC proto-oncogene. The SRC gene encodes a non-receptor protein tyrosine kinase that participates in multiple signaling pathways involved in gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, cell migration, and transformation; somatic mutations of SRC are implicated in multiple cancers. There is a single Drosophila gene orthologous to human CSK, Dmel\Csk, for which classical loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Csk is also orthologous to the human gene MATK.

Results using this system and a similar system (see cancer, multiple, RAS-SRC-related, FBhh0000666) support the hypothesis that differing levels of SRC activity have different results. It is postulated that SRC activity plays two separable roles during tumor maturation: early low levels of SRC contribute to tumor overgrowth, whereas later high levels of SRC, coupled with other oncogenes such as RAS, lead to invasive migration.

Animals homozygous for loss-of-function alleles of Dmel\Csk typically die during or before the pupal stage; larval body mass and larval structures are greatly enlarged. Physical and genetic interactions for Dmel\Csk have been described; see below and in the gene report for Csk. The human CSK gene has not been introduced into flies.

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.

[updated Nov. 2018 by FlyBase; FBrf0222196]