Forchlorfenuron disrupts SEPT9_i1 filaments and inhibits HIF-1
| Autor: | Maya Golan, Dikla Vardi-Oknin, Nicola J. Mabjeesh |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Proteasome Endopeptidase Complex
Transcription Genetic Immunoprecipitation Carcinogenesis Pyridines Protein subunit lcsh:Medicine Septin Ubiquitin Downregulation and upregulation Cell Movement Cell Line Tumor Humans Protein Isoforms Cytoskeleton lcsh:Science Transcription factor Cell Proliferation Multidisciplinary biology Phenylurea Compounds lcsh:R Hypoxia-Inducible Factor 1 alpha Subunit Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Biochemistry Proteasome Proteolysis biology.protein lcsh:Q Protein Processing Post-Translational Septins Subcellular Fractions Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 8, p e73179 (2013) |
| ISSN: | 1932-6203 |
| Popis: | Forchlorfenuron (FCF) is a synthetic plant cytokinin that has been shown to alter yeast and mammalian septin organization. Septins are a highly conserved family of GTP-binding cytoskeletal proteins. Mammalian septins are involved in diverse cellular processes including tumorigenesis. We have been studying the interaction between septin 9 isoform 1 (SEPT9_i1) and hypoxia inducible factor-1α (HIF-1α), the oxygen regulated subunit of HIF-1. HIF-1 is a key transcription factor in the hypoxic responses pathway, and its activation has been observed in carcinogenesis and numerous cancers. SEPT9_i1/HIF-1α interaction plays an important role in upregulation of HIF-1 transcriptional activity by preventing HIF-1α’s ubiquitination and degradation leading to increased tumor growth and angiogenesis. We tested the hypothesis whether FCF affects SEPT9_i1 filamentous structures and consequently HIF-1 pathway in cancer cells. We showed that FCF suppresses tumorigenic properties, including proliferation, migration and transformation, in prostate cancer cells. FCF did not alter SEPT9_i1 steady state protein expression levels but it affected its filamentous structures and subcellular localization. FCF induced degradation of HIF-1α protein in a dose- and time-dependent manner. This inhibition was also shown in other common cancer types tested. Rapid degradation of HIF-1α protein levels was accompanied by respective inhibition in HIF-1α transcriptional activity. Moreover, HIF-1α protein half-life was markedly decreased in the presence of FCF compared with that in the absence of FCF. The FCF-induced degradation of HIF-1α was mediated in a significant part via the proteasome. To the best of our knowledge, this is the first demonstration of specific manipulation of septin filaments by pharmacological means having downstream inhibitory effects on the HIF-1 pathway. |
| Databáze: | OpenAIRE |
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