Project description:The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies.
Project description:Indole is an intercellular and interkingdom signaling molecule, which is widespread in diverse ecological niches. Caenorhabditis elegans is a bacterivorous nematode living in soil and compost environments and a useful model host for the study of host-microbe interactions. While various bacteria and some plants produce a large quantity of extracellular indole, little is known about the effects of indole, its derivatives, and indole-producing bacteria on behaviors in C. elegans and animals. Here, we show that C. elegans senses and moves toward indole and indole-producing bacteria, such as Escherichia coli, Shigella boydii, Providencia stuartii, and Klebsiella oxytoca, while avoids non-indole producing pathogenic bacteria. It was also found that indole-producing bacteria and non-indole-producing bacteria exert divergent effects on egg-laying behavior of C. elegans via indole. In addition, various indole derivatives also modulate chemotaxis, egg-laying behavior, and survival of C. elegans. In contrast, indole at a high concentration to kill C. elegans that has the ability to detoxify indole via oxidation and glucosylation, indicating predator-prey interactions via a double-edged molecule indole. Transcriptional analysis showed that indole markedly up-regulated gene expression of cytochrome P450 family, UDP-glucuronosyltransferase, glutathione S-transferase, which explained well the modification of indole in C. elegans, while down-regulated expression of collagen genes and F-box genes. Our findings suggest that indole and its derivatives are important interkingdom signaling molecules in bacteria-nematode interactions.