Computational analysis of prolyl hydroxylase domain-containing protein 2 (PHD2) mutations promoting polycythemia insurgence in humans

Minervini, Giovanni; Quaglia, Federica; Tosatto, Silvio C. E.

doi:10.1038/srep18716

Cited by 9 publications

(5 citation statements)

References 75 publications

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“…EPOR binds EPO upon phosphorylation-dependent conformational change mediated by JAK2 (Janus Kinase 2) [92]. Mutations of EPOR are causative of familiar erythrocytosis [93,94], which is also a common manifestation of either VHL disease [95] and hypoxia-sensing impairment [96][97][98]. Indeed, mutations of pVHL are also known to promote congenital erythrocytosis (e.g.…”

Section: Erythropoietin Receptormentioning

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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Section: Erythropoietin Receptormentioning

confidence: 99%

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

2020

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“…As far as we know, this is the first time this particular mutation is described. Also, according to the family studies and analysis in silico, this mutation is a pathogenic variant associated with the CE phenotype observed in this family .…”

Section: Discussionmentioning

confidence: 66%

Congenital erythrocytosis – discover of a new mutation in the EGLN1 gene

Barradas

Rodrigues

Ferreira

et al. 2018

Clinical Case Reports

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“…A protein which seems to be quite important to mention is LIM domaincontaining protein 1 (LIMD1). PHD2 binding interface responsible for interaction with LIMD1 has been suggested in bioinformatics investigation of erythrocytosis causative mutations in PHD2 [57]. Actually, LIMD1 was shown to form a complex with PHD2 and VHL in several cell types, including human embryonic kidney cells, probably enhancing the activity of both proteins and yielding efficient HIF(1)α proteasomal degradation [58].…”

Section: Other Protein Interactionsmentioning

confidence: 99%

Molecular Insights into the Oxygen-Sensing Pathway and Erythropoietin Expression Regulation in Erythropoiesis

Tomc

Debeljak

2021

IJMS

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Erythropoiesis is regulated by several factors, including the oxygen-sensing pathway as the main regulator of erythropoietin (EPO) synthesis in the kidney. The release of EPO from the kidney and its binding to the EPO receptor (EPOR) on erythrocyte progenitor cells in the bone marrow results in increased erythropoiesis. Any imbalance in these homeostatic mechanisms can lead to dysregulated erythropoiesis and hematological disorders. For example, mutations in genes encoding key players of oxygen-sensing pathway and regulation of EPO production (HIF-EPO pathway), namely VHL, EGLN, EPAS1 and EPO, are well known causative factors that contribute to the development of erythrocytosis. We aimed to investigate additional molecular mechanisms involved in the HIF-EPO pathway that correlate with erythropoiesis. To this end, we conducted an extensive literature search and used several in silico tools. We identified genes encoding transcription factors and proteins that control transcriptional activation or repression; genes encoding kinases, deacetylases, methyltransferases, conjugating enzymes, protein ligases, and proteases involved in post-translational modifications; and genes encoding nuclear transport receptors that regulate nuclear transport. All these genes may modulate the stability or activity of HIF2α and its partners in the HIF-EPO pathway, thus affecting EPO synthesis. The theoretical information we provide in this work can be a valuable tool for a better understanding of one of the most important regulatory pathways in the process of erythropoiesis. This knowledge is necessary to discover the causative factors that may contribute to the development of hematological diseases and improve current diagnostic and treatment solutions in this regard.

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Computational analysis of prolyl hydroxylase domain-containing protein 2 (PHD2) mutations promoting polycythemia insurgence in humans

Cited by 9 publications

References 75 publications

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

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

Congenital erythrocytosis – discover of a new mutation in the EGLN1 gene

Molecular Insights into the Oxygen-Sensing Pathway and Erythropoietin Expression Regulation in Erythropoiesis

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