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

Minervini, Giovanni; Lopreiato, Raffaele; Bortolotto, Raissa; Falconieri, Antonella; Sartori, Geppo; Tosatto, Silvio C. E.

doi:10.1038/srep46562

Cited by 8 publications

(14 citation statements)

References 77 publications

(101 reference statements)

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“…As the number of acidic repeats forming pVHL30 N-terminal tail increases from rodents to primates 22 , data suggest that the isoform-dependent MDM2/pVHL30 association could have specifically evolved in higher mammals. We further observed that the cluster of positive charges in region 329-351 appears counterbalanced by an opposed concentration of negative charges in region 410-433 (Figure S12), supporting the hypothesis that the two flanking sequences interact with the pVHL30 acidic N-terminus and β-domain, respectively, as pVHL β-domain presents a number of conserved positive residues mediating multiple protein-protein interactions 10,33,28 . Notably, MDM2 residues spanning 351-433 fragment includes six ATM (ataxia-telangiectasia mutated kinase) phosphorylation sites (i.e., S386, S395, S407, T419 S425, S429, Figure S12), strongly suggesting that post-translational modifications may operate as regulator of MDM2/pVHL30 association, e.g.…”

Section: Resultssupporting

confidence: 73%

“…Functional intersections between oxygen sensing, apoptosis and cell cycle regulation are well described in the literature 26,28,44,45 , although their functional inter-connection and mutual regulation are still debated. In particular, under prolonged hypoxia, p53 has been reported to accumulate in the cell, yielding a direct repression of HIF-1α transcriptional activity 46 .…”

Section: Discussionmentioning

confidence: 99%

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The E3 ubiquitin-protein ligase MDM2 is a novel interactor of the von Hippel-Lindau tumor suppressor

Falconieri

Minervini

Bortolotto

et al. 2020

Preprint

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Mutations of the von Hippel-Lindau (pVHL) tumor suppressor are causative of a familiar predisposition to develop different types of cancer. pVHL is mainly known for its role in regulating hypoxia-inducible factor 1-α (HIF-1α) degradation, thus modulating the hypoxia response. There are different pVHL isoforms, including pVHL30 and pVHL19. However, little is known about isoform-specific functions and protein-protein interactions. Integrating in silico predictions with in vitro and in vivo assays, we describe a novel interaction between pVHL and mouse double minute 2 homolog (MDM2). Importantly, we found that pVHL30, and not pVHL19, forms a complex with MDM2, and that the N-terminal acidic tail of pVHL30 is required for its association with MDM2.Further, we demonstrate that an intrinsically disordered region upstream of the tetramerization domain of MDM2 is responsible for its isoform-specific association with pVHL30. This region is highly conserved in higher mammals, including primates, similarly to what has been already proposed for the N-terminal tail of pVHL30. Finally, we show that overexpression of pVHL30 and MDM2 together reduces cell proliferation, suggesting a synergistic effect of these E3 ubiquitin ligases. Collectively, our data support the idea that pVHL30 plays a role in MDM2 regulation, suggesting a wider interplay among hypoxia sensing and cell cycle regulation. mainly localized in the nucleus and participating in the regulation of transcription in response to hypoxia and cellular stress. The second cluster was composed of seven proteins, including pVHL, and, as expected, it was linked to protein degradation. The last cluster was the most heterogeneous and included proteins associated with both hypoxia-and stress-response, e.g. nutrient deprivation and viral aggression. Of note, we found a number of experimentally validated interactions connecting all of these three clusters, suggesting that the hypoxia response is functionally interconnected with cell cycle regulation. Manually curated enrichment of protein-protein interactions across network nodes further extended the connection between clusters I and II.Considering the concept of "interactors of interactors", a well-established property of proteinprotein interaction networks 28,29 and the already validated physical interaction between pVHL, p53, and p14ARF, our in silico analysis predicts that MDM2 is a novel direct interactor of pVHL.

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Section: Resultssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

The E3 ubiquitin-protein ligase MDM2 is a novel interactor of the von Hippel-Lindau tumor suppressor

Falconieri

Minervini

Bortolotto

et al. 2020

Preprint

Self Cite

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“…As the number of acidic repeats forming pVHL30 N-terminal tail increases from rodents to primates 22 , data suggest that the isoform-dependent MDM2/pVHL30 association could have specifically evolved in higher mammals. We further observed that the cluster of positive charges in region 329-351 appears counterbalanced by an opposed concentration of negative charges in region 410-433 ( Figure S11), supporting the hypothesis that the two flanking sequences interact with the pVHL30 acidic N-terminus and β-domain, respectively, as pVHL β-domain presents a number of conserved positive residues mediating multiple protein-protein interactions 10,28,33 . Notably, MDM2 residues spanning 351-433 fragment includes six ATM (ataxia-telangiectasia mutated kinase) phosphorylation sites (i.e.…”

Section: Resultssupporting

confidence: 73%

“…Manually curated enrichment of protein-protein interactions across network nodes further extended the connection between clusters I and II. Considering the concept of "interactors of interactors", a well-established property of protein-protein interaction networks 28,29 and the already validated physical interaction between pVHL, p53, and p14ARF, our in silico analysis predicts that MDM2 is a novel direct interactor of pVHL.…”

Section: Resultsmentioning

confidence: 95%

The E3 ubiquitin-protein ligase MDM2 is a novel interactor of the von Hippel–Lindau tumor suppressor

Falconieri

Minervini

Bortolotto

et al. 2020

Sci Rep

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Mutations of the von Hippel–Lindau (pVHL) tumor suppressor are causative of a familiar predisposition to develop different types of cancer. pVHL is mainly known for its role in regulating hypoxia-inducible factor 1 α (HIF-1α) degradation, thus modulating the hypoxia response. There are different pVHL isoforms, including pVHL30 and pVHL19. However, little is known about isoform-specific functions and protein–protein interactions. Integrating in silico predictions with in vitro and in vivo assays, we describe a novel interaction between pVHL and mouse double minute 2 homolog (MDM2). We found that pVHL30, and not pVHL19, forms a complex with MDM2, and that the N-terminal acidic tail of pVHL30 is required for its association with MDM2. Further, we demonstrate that an intrinsically disordered region upstream of the tetramerization domain of MDM2 is responsible for its isoform-specific association with pVHL30. This region is highly conserved in higher mammals, including primates, similarly to what has been already shown for the N-terminal tail of pVHL30. Finally, we show that overexpression of pVHL30 and MDM2 together reduces cell metabolic activity and necrosis, suggesting a synergistic effect of these E3 ubiquitin ligases. Collectively, our data show an isoform-specific interaction of pVHL with MDM2, suggesting an interplay between these two E3 ubiquitin ligases.

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“…Further, correlation between pVHL and kinase activity is not limited to the direct association with kinases. In a previous work, we reported the direct interaction between pVHL and the CDKN1 kinase inhibitor protein family [ 57 ]. We found that the CDKN1 proteins share a conserved region mimicking the HIF-1 α motif responsible for pVHL binding.…”

Section: Introductionmentioning

confidence: 99%

The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer

2020

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The von Hippel–Lindau protein (pVHL) is a tumour suppressor mainly known for its role as master regulator of hypoxia-inducible factor (HIF) activity. Functional inactivation of pVHL is causative of the von Hippel–Lindau disease, an inherited predisposition to develop different cancers. Due to its impact on human health, pVHL has been widely studied in the last few decades. However, investigations mostly focus on its role in degrading HIFs, whereas alternative pVHL protein–protein interactions and functions are insistently surfacing in the literature. In this review, we analyse these almost neglected functions by dissecting specific conditions in which pVHL is proposed to have differential roles in promoting cancer. We reviewed its role in regulating phosphorylation as a number of works suggest pVHL to act as an inhibitor by either degrading or promoting downregulation of specific kinases. Further, we summarize hypoxia-dependent and -independent pVHL interactions with multiple protein partners and discuss their implications in tumorigenesis.

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

Cited by 8 publications

References 77 publications

The E3 ubiquitin-protein ligase MDM2 is a novel interactor of the von Hippel-Lindau tumor suppressor

The E3 ubiquitin-protein ligase MDM2 is a novel interactor of the von Hippel-Lindau tumor suppressor

The E3 ubiquitin-protein ligase MDM2 is a novel interactor of the von Hippel–Lindau tumor suppressor

The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer

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