A multigenic model of cancer has been developed using the human S100A4 gene in combination with an activated form of the Drosophila Ras85D gene. S100A4 is described as a metastasis-inducing but not a tumor-initiating oncogene, functioning to increase tumor progression and metastasis. S100A4 encodes a member of the S100 family of calcium-binding proteins; S100 proteins interact with a wide range of target proteins involved in regulation of numerous different cellular processes. The S100 gene family appears to be confined to vertebrates, thus there is no gene orthologous to S100A4 in Drosophila.
Two UAS constructs of the Hsap\S100A4 gene have been introduced into flies: a wild-type human gene and an inactive deletion mutation. These have been expressed in the optic lobes of the larval brain, with and without co-expression of activated Dmel\Ras85D. Wild-type Hsap\S100A4 expressed alone failed to produced a tumor phenotype. Activated Ras85D expressed alone produced tumors confined to the optic lobes ~70% of the time; in the remaining 30%, tumors were observed to extend into the ventral nerve cord (VNC). Hsap\S100A4 co-expressed with activated Ras85D resulted in a dramatic increase in metastatic phenotypes: metastasis to the VNC was observed in almost 90% of cases; metastasis to other organs was also observed. No increase is metastatic phenotypes was observed for activated Ras85D when co-expressed with the Hsap\S100A4 deletion mutation.
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, Ras85DV12, 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 report 'cancer, multiple, RAS-related' (FBhh0000474).
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, Ras85DV12. This allele is usually lethal during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85DV12 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]
S100A4 is a metastasis-inducing but not a tumor-initiating oncogene. Detection of S100A4 expression is a candidate biomarker in cancer early diagnosis (Fei et al., 2017; pubmed:29069865).
Chromosomal rearrangements and altered expression of S100A4 have been implicated in tumor metastasis. [Gene Cards, 2018.11.02]
S100A4 is one of 22 S100 genes clustered at chromosome locus 1q21, a region frequently rearranged in cancers (Chen et al., 2014; pubmed:24660101).
S100A4 shows no enzymatic activity but exerts its biological function via the interaction with target proteins (Fei et al., 2017; pubmed:29069865).
The protein encoded by S100A4 is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and are involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. [Gene Cards, 2018.11.02]
Upon calcium binding, most S100 proteins undergo a conformational change, thus allowing the protein to interact with the different protein targets (Chen et al., 2014; pubmed:24660101; Fei et al., 2017; pubmed:29069865).
The is no gene orthologous to S100A4 in Drosophila.
