Involvement of E3 Ligases and Deubiquitinases in the Control of HIF-α Subunit Abundance

Kubaichuk, Kateryna; Kietzmann, Thomas

doi:10.3390/cells8060598

Cited by 24 publications

(32 citation statements)

References 212 publications

(175 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ubiquitination is another highly dynamic process, in the oxygen-sensing pathway best known for its role in VHL-HIFα proteasomal degradation. Apart from that, ubiquitin modification is more complex with diverse functions and can affect other proteins than HIFα [42]. VHL itself can be subjected to proteasomal degradation which consequently results in HIFα stability.…”

Section: Post-translational Modificationsmentioning

confidence: 99%

“…VHL itself can be subjected to proteasomal degradation which consequently results in HIFα stability. Several factors that regulate VHL abundance and function have been identified, such as ubiquitin ligases Cadherin 1, WD repeat and SOCS box-containing protein 1 (WSB1), hSMURF1, and ubiquitin-conjugating enzyme E2-EPF [42][43][44][45]. Although WSB1 and E2-EPF expression is associated with cancer progression, they were both identified to interact with VHL and promote its ubiquitination and proteasomal degradation also in normoxic conditions in the human embryonic kidney or renal carcinoma cells [44,45].…”

Section: Post-translational Modificationsmentioning

confidence: 99%

“…For example, USP8 and USP29 can prevent VHL-mediated degradation of ubiquitinated HIF2α and thus increase its stability [46,47]. Probable ubiquitin carboxyl-terminal hydrolase FAF-X (USP9X) deubiquitylates hSMURF1, which targets VHL for proteasomal degradation, resulting in reduced VHL protein levels and stable HIFα protein [42].…”

Section: Post-translational Modificationsmentioning

confidence: 99%

See 2 more Smart Citations

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

Tomc

Debeljak

2021

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Post-translational Modificationsmentioning

confidence: 99%

Section: Post-translational Modificationsmentioning

confidence: 99%

Section: Post-translational Modificationsmentioning

confidence: 99%

See 1 more Smart Citation

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

Tomc

Debeljak

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…The reversible regulation of Ub by E3 ligases and DUBs has received increasing attention for several diseases, including cancers [ 34 , 35 , 36 , 37 ]. The ubiquitination pathway affects many tumor-suppressor proteins, including p53 and its homologs, p63 and p73 [ 38 ].…”

Section: Ubiquitination-dependent P73 Inhibitionmentioning

confidence: 99%

Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors

Omran

Dalhat

Abdullah

et al. 2021

Cancers

View full text Add to dashboard Cite

The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status.

show abstract

“…HIFα proteins can be directly or indirectly modulated by post-translational modifications. Beside to O 2 dependent hydroxylation, also phosphorylation [35][36][37], acetylation [38,39], methylation [40], ubiquitination [41] and sumoylation [42,43] have been found to affect its transcriptional activity or stability. However, many of these post-translational mechanisms do not require O 2 as a co-factor.…”

Section: Regulation At the Protein Level Protein Interactions And Modificationsmentioning

confidence: 99%

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Tomc

Debeljak

2021

Genes

View full text Add to dashboard Cite

Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

show abstract

Involvement of E3 Ligases and Deubiquitinases in the Control of HIF-α Subunit Abundance

Cited by 24 publications

References 212 publications

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

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

Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Contact Info

Product

Resources

About