Article ; Online: Novel interactions of the von Hippel-Lindau (pVHL) tumor suppressor with the CDKN1 family of cell cycle inhibitors.
2017 Volume 7, Page(s) 46562
Abstract: Germline inactivation of the von Hippel-Lindau (VHL) tumor suppressor predisposes patients ... inhibitor family CDKN1 (p21, p27 and p57). Bioinformatics analysis, yeast two-hybrid screening and ... far from understood. Here, we present novel interactions between pVHL and the cyclin-dependent kinase ...
Abstract | 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. |
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MeSH term(s) | Amino Acid Sequence ; Cell Cycle/genetics ; Cell Hypoxia ; Cyclin-Dependent Kinase Inhibitor Proteins/genetics ; Cyclin-Dependent Kinase Inhibitor Proteins/metabolism ; Genes, Tumor Suppressor ; HEK293 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Molecular Dynamics Simulation ; Mutation ; Protein Binding ; Protein Interaction Maps ; Sequence Homology, Amino Acid ; Two-Hybrid System Techniques ; Von Hippel-Lindau Tumor Suppressor Protein/genetics ; Von Hippel-Lindau Tumor Suppressor Protein/metabolism |
Chemical Substances | Cyclin-Dependent Kinase Inhibitor Proteins ; Hypoxia-Inducible Factor 1, alpha Subunit ; Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27) ; VHL protein, human (EC 6.3.2.-) |
Language | English |
Publishing date | 2017-04-20 |
Publishing country | England |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 2615211-3 |
ISSN | 2045-2322 ; 2045-2322 |
ISSN (online) | 2045-2322 |
ISSN | 2045-2322 |
DOI | 10.1038/srep46562 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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