Novel interactions of the von Hippel-Lindau (pVHL) tumor suppressor with the CDKN1 family of cell cycle inhibitors
| Autor: | Silvio C. E. Tosatto, Antonella Falconieri, Geppo Sartori, Raissa Bortolotto, Giovanni Minervini, Raffaele Lopreiato |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Hypoxia-Inducible Factor 1 Plasma protein binding Biology Molecular Dynamics Simulation urologic and male genital diseases Germline Article law.invention 03 medical and health sciences law Two-Hybrid System Techniques Humans Genes Tumor Suppressor Amino Acid Sequence Protein Interaction Maps Transcription factor Cyclin-Dependent Kinase Inhibitor Proteins Multidisciplinary Sequence Homology Amino Acid Kinase HEK 293 cells Cell Cycle Cell cycle Hypoxia-Inducible Factor 1 alpha Subunit Cell Hypoxia Cell biology 030104 developmental biology HEK293 Cells Von Hippel-Lindau Tumor Suppressor Protein Mutation Suppressor Protein Binding |
| Zdroj: | Scientific Reports |
| Popis: | Germline inactivation of the von Hippel-Lindau (VHL) tumor suppressor predisposes patients to develop different highly vascularized cancers. pVHL targets the hypoxia-inducible transcription factor (HIF-1α) for degradation, modulating the activation of various genes involved in hypoxia response. Hypoxia plays a relevant role in regulating cell cycle progression, inducing growth arrest in cells exposed to prolonged oxygen deprivation. However, the exact molecular details driving this transition are far from understood. Here, we present novel interactions between pVHL and the cyclin-dependent kinase inhibitor family CDKN1 (p21, p27 and p57). Bioinformatics analysis, yeast two-hybrid screening and co-immunoprecipitation assays were used to predict, dissect and validate the interactions. We found that the CDKN1 proteins share a conserved region mimicking the HIF-1α motif responsible for pVHL binding. Intriguingly, a p27 site-specific mutation associated to cancer is shown to modulate this novel interaction. Our findings suggest a new connection between the pathways regulating hypoxia and cell cycle progression. |
| Databáze: | OpenAIRE |
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