JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism
| Autor: | Hui Miao, Shenaz Khan, Karen L. Wu |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Physiology
medicine.medical_treatment Blotting Western Suppressor of Cytokine Signaling Proteins Biology urologic and male genital diseases Transfection Culture Media Serum-Free law.invention Cell Line Cancer syndrome Suppressor of Cytokine Signaling 1 Protein law Renal cell carcinoma medicine Humans Immunoprecipitation Neoplasm Invasiveness neoplasms Carcinoma Renal Cell Janus Kinases Wound Healing Kinase Cancer medicine.disease female genital diseases and pregnancy complications Kidney Neoplasms Cytokine Von Hippel-Lindau Tumor Suppressor Protein Immunology Cancer research Suppressor Cytokines Indicators and Reagents Hypoxia-Inducible Factor 1 Signal transduction Janus kinase Plasmids |
| Zdroj: | American journal of physiology. Renal physiology. 293(6) |
| ISSN: | 1931-857X |
| Popis: | von Hippel-Lindau (VHL) disease is a cancer syndrome, which includes renal cell carcinoma (RCC), and is caused by VHL mutations. Most, but not all VHL phenotypes are due to failure of mutant VHL to regulate constitutive proteolysis of hypoxia-inducible factors (HIFs). Janus kinases (JAK1, 2, 3, and TYK2) promote cell survival and proliferation, processes tightly controlled by SOCS proteins, which have sequence and structural homology to VHL. We hypothesized that in VHL disease, RCC pathogenesis results from enhanced SOCS1 degradation, leading to upregulated JAK activity. We find that baseline JAK2, JAK3, and TYK2 activities are increased in RCC cell lines, even after serum deprivation or coincubation with cytokine inhibitors. Furthermore, JAK activity is sustained in RCC stably expressing HIF2α shRNA. Invasion through Matrigel and migration in wound-healing assays, in vitro correlates of metastasis, are significantly greater in VHL mutant RCC compared with wild-type cells, and blocked by dominant-negative JAK expression or JAK inhibitors. Finally, we observe enhanced SOCS2/SOCS1 coprecipitation and reduced SOCS1 expression due to proteasomal degradation in VHL-null RCC compared with wild-type cells. The data support a new HIF-independent mechanism of RCC metastasis, whereby SOCS2 recruits SOCS1 for ubiquitination and proteasome degradation, which lead to unrestricted JAK-dependent RCC invasion. In addition to commonly proposed RCC treatment strategies that target HIFs, our data suggest that JAK inhibition represents an alternative therapeutic approach. |
| Databáze: | OpenAIRE |
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