• cancer

Using an activated mutation in the fly Ras85D gene in a screen for genes involved in tumor progression, the Drosophila Vps-C complex gene dor was identified. Descriptions of hereditary phenotypes of an allele of this gene are the first published observations of tumor-like melanotic masses in flies (in 1918!). Loss-of-function mutations of dor promote overgrowth and invasive phenotypes in clones of Ras85D^V12 cells; impaired lysosomal degradation is observed. Dmel\dor is orthologous to the human gene VPS18. Additional components of the Drosophila Vps-C complex, car (orthologous to human VPS33A) and Vps16A (orthologous to human VPS16), have been tested; loss-of-function mutations of either of these genes in clones of Ras85D^V12 cells also result in neoplastic phenotypes. Classical loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for the three fly genes (dor, car and Vps16A).

Genes of the Vps-C complex were initially identified in yeast. Four genes, Vps11, Vps16, Vps18, and Vps33 form the Vps-C core complex and are highly conserved across eukaryotes. This complex is essential for late endosome and lysosome assembly and for numerous endolysosomal trafficking pathways, including the terminal stages of autophagy. Human VPS33A is implicated in the disease mucopolysaccharidosis-plus syndrome (MIM:617303).

None of the genes encoding the proteins of the human Vps-C core complex has been introduced into flies.

Severe loss-of-function mutations in any of the three Drosophila genes identified in this work, dor, car and Vps16A, result in larval lethality. Assayed in larvae, somatic clones, or RNAi-targeted tissues, abnormalities of endosome and lysosome structure and impaired autophagy are observed. Milder mutations result in dark eye color phenotypes. Physical and genetic interactions have been described for each of the three genes; see below and in the respective gene reports.

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' (FBhh0000474).

[updated Jun. 2019 by FlyBase; FBrf0222196]