De-regulation of JNK and JAK/STAT signaling in ESCRT-II mutant tissues cooperatively contributes to neoplastic tumorigenesis

• Published in: PloS one 2013-02, Vol.8 (2), p.e56021
• Main Authors: Woodfield, Sarah E, Graves, Hillary K, Hernandez, Jacob A, Bergmann, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis; Biochemistry; Biology; c-Jun protein; Cancer; Cancer genetics; Cell cycle; Cell growth; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cloning; Developmental biology; Drosophila; Endocytosis; Endosomal Sorting Complexes Required for Transport - genetics; Endosomal Sorting Complexes Required for Transport - metabolism; Genes; Genetic transformation; Genomics; Inhibition; Insects; Janus kinase; Janus Kinases - genetics; Janus Kinases - metabolism; JNK protein; Kinases; Ligands; MAP Kinase Signaling System - physiology; Medicine; Molecular biology; Mutants; Mutation; Protein transport; Protein Transport - physiology; Proteins; Proteomics; Receptors, Notch - genetics; Receptors, Notch - metabolism; Signal Transduction - physiology; Signaling; STAT Transcription Factors - genetics; STAT Transcription Factors - metabolism; Tissues; Transcription factors; Transformation; Tumor suppressor genes; Tumorigenesis; Tumors; Up-Regulation - physiology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0056021

Multiple genes involved in endocytosis and endosomal protein trafficking in Drosophila have been shown to function as neoplastic tumor suppressor genes (nTSGs), including Endosomal Sorting Complex Required for Transport-II (ESCRT-II) components vacuolar protein sorting 22 (vps22), vps25, and vps36. However, most studies of endocytic nTSGs have been done in mosaic tissues containing both mutant and non-mutant populations of cells, and interactions among mutant and non-mutant cells greatly influence the final phenotype. Thus, the true autonomous phenotype of tissues mutant for endocytic nTSGs remains unclear. Here, we show that tissues predominantly mutant for ESCRT-II components display characteristics of neoplastic transformation and then undergo apoptosis. These neoplastic tissues show upregulation of c-Jun N-terminal Kinase (JNK), Notch, and Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling. Significantly, while inhibition of JNK signaling in mutant tissues partially inhibits proliferation, inhibition of JAK/STAT signaling rescues other aspects of the neoplastic phenotype. This is the first rigorous study of tissues predominantly mutant for endocytic nTSGs and provides clear evidence for cooperation among de-regulated signaling pathways leading to tumorigenesis.