Adding structural information to the von Hippel–Lindau (VHL) tumor suppressor interaction network

Leonardi, Emanuela; Murgia, Alessandra; Tosatto, Silvio C. E.

doi:10.1016/j.febslet.2009.10.070

Cited by 26 publications

(39 citation statements)

References 63 publications

(77 reference statements)

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“…We found that both GST-pVHL 1–173 and GST-pVHL 1–114 were able to bind p45 AUF1 , indicating that deletion of the Elongin C-binding pVHL α domain did not affect AUF1 binding (Figure 4B). We also tested GST-pVHL β domain mutations that correspond to truncation at each of the first 4 β sheets as indicated in Figure 4B (3, 4). Deletion of β sheet 4 (construct 1–101) and β sheet 3 (construct 1–89) did not disrupt p45 AUF1 binding, while p45 AUF1 binding to the GST-pVHL 1–78 construct was diminished (Figure 4B), suggesting that AUF1 requires either β sheet 2, the loop between β sheet 1 and 2, or both for binding to pVHL.…”

Section: Resultsmentioning

confidence: 99%

Association of the von Hippel–Lindau Protein with AUF1 and Posttranscriptional Regulation of VEGFA mRNA

Xiao

Brown

Gong

et al. 2012

Molecular Cancer Research

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The von Hippel-Lindau (VHL) tumor suppressor gene product is the recognition component of an E3 ubiquitin ligase and is inactivated in patients with VHL disease and in most sporadic clear cell renal carcinomas (RCC). pVHL controls oxygen-responsive gene expression at the transcriptional and post-transcriptional levels. The vascular endothelial growth factor A (VEGFA) mRNA contains AU-rich elements (AREs) in the 3' untranslated region, and mRNA stability or decay is determined through ARE-associated RNA binding factors. We show here that levels of the ARE binding factor, AUF1, are regulated by pVHL and by hypoxia. pVHL and AUF1 stably associate with each other in cells and AUF1 is a ubiquitylation target of pVHL. AUF1 and another RNA binding protein, HuR, bind to VEGFA ARE RNA. Ribonucleoprotein (RNP)-immunoprecipitations showed that pVHL associates indirectly with VEGFA mRNA through AUF1 and/or HuR, and this complex is associated with VEGFA mRNA decay under normoxic conditions. Under hypoxic conditions pVHL is downregulated, while AUF1 and HuR binding to VEGF mRNA is maintained, and this complex is associated with stabilized mRNA. These studies suggest that AUF1 and HuR bind to VEGFA ARE RNA under both normoxic and hypoxic conditions, and that a pVHL-RNP complex determines VEGFA mRNA decay. These studies further implicate the ubiquitin-proteasome system in ARE-mediated RNA degradation.

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Section: Resultsmentioning

confidence: 99%

Association of the von Hippel–Lindau Protein with AUF1 and Posttranscriptional Regulation of VEGFA mRNA

Xiao

Brown

Gong

et al. 2012

Molecular Cancer Research

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“…In this context, interaction with the CDKN1 protein family may have evolved to allow transmission of a generic hypoxic signal to other signaling pathways, re-using the same pVHL adaptor protein. Intriguingly, the same pVHL region5354 mediates its association with over 40 proteins beyond HIF-1/2α54, implying multiple factors in dynamic competition to alternatively associate unbound pVHL in the cell.…”

Section: Discussionmentioning

confidence: 99%

Novel interactions of the von Hippel-Lindau (pVHL) tumor suppressor with the CDKN1 family of cell cycle inhibitors

Minervini

Lopreiato

Bortolotto

et al. 2017

Sci Rep

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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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“…The binding domains of HIF1/2α (amino acid 67-117), p53 (aa 154-163) and Elongin C (aa 157-171) were assessed as described by Leonardi et al [49]. We selected four mutations that were located in the overlap of p53 and EloC binding domains of pVHL (aa 157-163): three were predicted to have no or little impact on the protein stability (Leu158Val, Arg161Gln, Cys162Arg, mild impact) and one was predicted to highly destabilize pVHL (Arg161Pro, high impact).…”

Section: Methodsmentioning

confidence: 99%

VHL missense mutations in the p53 binding domain show different effects on p53 signaling and HIFα degradation in clear cell renal cell carcinoma

et al. 2016

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Clear cell Renal Cell Carcinoma (ccRCC) formation is connected to functional loss of the von Hippel-Lindau (VHL) gene. Recent data identified its gene product, pVHL, as a multifunctional adaptor protein which interacts with HIFα subunits but also with the tumor suppressor p53. p53 is hardly expressed and rarely mutated in most ccRCC. We showed that low and absent p53 expression correlated with the severity of VHL mutations in 262 analyzed ccRCC tissues. In contrast to nonsense and frameshift mutations which abrogate virtually all pVHL functions, missense mutations may rather influence one or few functions. Therefore, we focused on four VHL missense mutations, which affect the overlapping pVHL binding sites of p53 and Elongin C, by investigating their impact on HIFα degradation, p53 expression and signaling, as well as on cellular behavior using ccRCC cell lines and tissues. TP53 mRNA and its effector targets p21, Bax and Noxa, were altered both in engineered cell lines and in tumor tissues which carried the same missense mutations. Two of these mutations were not able to degrade HIFα whereas the remaining two mutations led to HIFα downregulation, suggesting the latter are p53 binding site-specific. The selected VHL missense mutations further enhanced tumor cell survival, but had no effects on cell proliferation. Whereas Sunitinib was able to efficiently reduce cell proliferation, Camptothecin was additionally able to increase apoptotic activity of the tumor cells. It is concluded that systematic characterization of the VHL mutation status may help optimizing targeted therapy for patients with metastatic ccRCC.

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Adding structural information to the von Hippel–Lindau (VHL) tumor suppressor interaction network

Cited by 26 publications

References 63 publications

Association of the von Hippel–Lindau Protein with AUF1 and Posttranscriptional Regulation of VEGFA mRNA

Association of the von Hippel–Lindau Protein with AUF1 and Posttranscriptional Regulation of VEGFA mRNA

Novel interactions of the von Hippel-Lindau (pVHL) tumor suppressor with the CDKN1 family of cell cycle inhibitors

VHL missense mutations in the p53 binding domain show different effects on p53 signaling and HIFα degradation in clear cell renal cell carcinoma

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