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Article ; Online: Ubiquitin-Dependent and Independent Proteasomal Degradation in Host-Pathogen Interactions.

Bialek, Wojciech / Collawn, James F / Bartoszewski, Rafal

2023 Volume 28, Issue 18

Abstract: Ubiquitin, a small protein, is well known for tagging target proteins through a cascade of enzymatic reactions that lead to protein degradation. The ubiquitin tag, apart from its signaling role, is paramount in destabilizing the modified protein. Here, ... ...

Abstract	Ubiquitin, a small protein, is well known for tagging target proteins through a cascade of enzymatic reactions that lead to protein degradation. The ubiquitin tag, apart from its signaling role, is paramount in destabilizing the modified protein. Here, we explore the complex role of ubiquitin-mediated protein destabilization in the intricate proteolysis process by the 26S proteasome. In addition, the significance of the so-called ubiquitin-independent pathway and the role of the 20S proteasome are considered. Next, we discuss the ubiquitin-proteasome system's interplay with pathogenic microorganisms and how the microorganisms manipulate this system to establish infection by a range of elaborate pathways to evade or counteract host responses. Finally, we focus on the mechanisms that rely either on (i) hijacking the host and on delivering pathogenic E3 ligases and deubiquitinases that promote the degradation of host proteins, or (ii) counteracting host responses through the stabilization of pathogenic effector proteins.
Language	English
Publishing date	2023-09-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules28186740
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: HIF-1-Induced hsa-miR-429: Understanding Its Direct Targets as the Key to Developing Cancer Diagnostics and Therapies.

Bartoszewska, Sylwia / Sławski, Jakub / Collawn, James F / Bartoszewski, Rafal

Cancers

2023 Volume 15, Issue 11

Abstract: MicroRNAs (miRNAs) play a critical role in the regulation of mRNA stability and translation. In spite of our present knowledge on the mechanisms of mRNA regulation by miRNAs, the utilization and translation of these ncRNAs into clinical applications have ...

Abstract	MicroRNAs (miRNAs) play a critical role in the regulation of mRNA stability and translation. In spite of our present knowledge on the mechanisms of mRNA regulation by miRNAs, the utilization and translation of these ncRNAs into clinical applications have been problematic. Using hsa-miR-429 as an example, we discuss the limitations encountered in the development of efficient miRNA-related therapies and diagnostic approaches. The miR-200 family members, which include hsa-miR-429, have been shown to be dysregulated in different types of cancer. Although these miR-200 family members have been shown to function in suppressing epithelial-to-mesenchymal transition, tumor metastasis, and chemoresistance, the experimental results have often been contradictory. These complications involve not only the complex networks involving these noncoding RNAs, but also the problem of identifying false positives. To overcome these limitations, a more comprehensive research strategy is needed to increase our understanding of the mechanisms underlying their biological role in mRNA regulation. Here, we provide a literature analysis of the verified hsa-miR-429 targets in various human research models. A meta-analysis of this work is presented to provide better insights into the role of hsa-miR-429 in cancer diagnosis and any potential therapeutic approach.
Language	English
Publishing date	2023-05-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15112903
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment.

Bartoszewska, Sylwia / Collawn, James F / Bartoszewski, Rafal

Cancers

2022 Volume 14, Issue 19

Abstract: Despite our understanding of the unfolded protein response (UPR) pathways, the crosstalk between the UPR and the complex signaling networks that different cancers utilize for cell survival remains to be, in most cases, a difficult research barrier. A ... ...

Abstract	Despite our understanding of the unfolded protein response (UPR) pathways, the crosstalk between the UPR and the complex signaling networks that different cancers utilize for cell survival remains to be, in most cases, a difficult research barrier. A major problem is the constant variability of different cancer types and the different stages of cancer as well as the complexity of the tumor microenvironments (TME). This complexity often leads to apparently contradictory results. Furthermore, the majority of the studies that have been conducted have utilized two-dimensional in vitro cultures of cancer cells that were exposed to continuous hypoxia, and this approach may not mimic the dynamic and cyclic conditions that are found in solid tumors. Here, we discuss the role of intermittent hypoxia, one of inducers of the UPR in the cellular component of TME, and the way in which intermittent hypoxia induces high levels of reactive oxygen species, the activation of the UPR, and the way in which cancer cells modulate the UPR to aid in their survival. Although the past decade has resulted in defining the complex, novel non-coding RNA-based regulatory networks that modulate the means by which hypoxia influences the UPR, we are now just to beginning to understand some of the connections between hypoxia, the UPR, and the TME.
Language	English
Publishing date	2022-10-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14194870
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The Unfolded Protein Response: A Double-Edged Sword for Brain Health.

Gebert, Magdalena / Sławski, Jakub / Kalinowski, Leszek / Collawn, James F / Bartoszewski, Rafal

Antioxidants (Basel, Switzerland)

2023 Volume 12, Issue 8

Abstract: Efficient brain function requires as much as 20% of the total oxygen intake to support normal neuronal cell function. This level of oxygen usage, however, leads to the generation of free radicals, and thus can lead to oxidative stress and potentially to ... ...

Abstract	Efficient brain function requires as much as 20% of the total oxygen intake to support normal neuronal cell function. This level of oxygen usage, however, leads to the generation of free radicals, and thus can lead to oxidative stress and potentially to age-related cognitive decay and even neurodegenerative diseases. The regulation of this system requires a complex monitoring network to maintain proper oxygen homeostasis. Furthermore, the high content of mitochondria in the brain has elevated glucose demands, and thus requires a normal redox balance. Maintaining this is mediated by adaptive stress response pathways that permit cells to survive oxidative stress and to minimize cellular damage. These stress pathways rely on the proper function of the endoplasmic reticulum (ER) and the activation of the unfolded protein response (UPR), a cellular pathway responsible for normal ER function and cell survival. Interestingly, the UPR has two opposing signaling pathways, one that promotes cell survival and one that induces apoptosis. In this narrative review, we discuss the opposing roles of the UPR signaling pathways and how a better understanding of these stress pathways could potentially allow for the development of effective strategies to prevent age-related cognitive decay as well as treat neurodegenerative diseases.
Language	English
Publishing date	2023-08-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12081648
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Editorial focus: understanding off-target effects as the key to successful RNAi therapy.

Bartoszewski, Rafal / Sikorski, Aleksander F

Cellular & molecular biology letters

2019 Volume 24, Page(s) 69

Abstract: With the first RNA interference (RNAi) drug (ONPATTRO (patisiran)) on the market, we witness the RNAi therapy field reaching a critical turning point, when further improvements in drug candidate design and delivery pipelines should enable fast delivery ... ...

Abstract	With the first RNA interference (RNAi) drug (ONPATTRO (patisiran)) on the market, we witness the RNAi therapy field reaching a critical turning point, when further improvements in drug candidate design and delivery pipelines should enable fast delivery of novel life changing treatments to patients. Nevertheless, ignoring parallel development of RNAi dedicated in vitro pharmacological profiling aiming to identify undesirable off-target activity may slow down or halt progress in the RNAi field. Since academic research is currently fueling the RNAi development pipeline with new therapeutic options, the objective of this article is to briefly summarize the basics of RNAi therapy, as well as to discuss how to translate basic research into better understanding of related drug candidate safety profiles early in the process.
MeSH term(s)	Amyloid Neuropathies/genetics ; Amyloid Neuropathies/metabolism ; Amyloid Neuropathies/pathology ; Amyloid Neuropathies/therapy ; Animals ; Gene Transfer Techniques ; Humans ; MicroRNAs/antagonists & inhibitors ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Molecular Targeted Therapy/methods ; RNA Interference ; RNA Stability ; RNA, Messenger/antagonists & inhibitors ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; RNA, Small Interfering/therapeutic use ; RNA, Untranslated/antagonists & inhibitors ; RNA, Untranslated/genetics ; RNA, Untranslated/metabolism ; RNA-Induced Silencing Complex/genetics ; RNA-Induced Silencing Complex/metabolism ; RNAi Therapeutics/methods
Chemical Substances	MicroRNAs ; RNA, Messenger ; RNA, Small Interfering ; RNA, Untranslated ; RNA-Induced Silencing Complex ; patisiran (50FKX8CB2Y)
Language	English
Publishing date	2019-12-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2108724-6
ISSN	1689-1392 ; 1689-1392
ISSN (online)	1689-1392
ISSN	1689-1392
DOI	10.1186/s11658-019-0196-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Regulation of the HIF switch in human endothelial and cancer cells.

Slawski, Jakub / Jaśkiewicz, Maciej / Barton, Anna / Kozioł, Sylwia / Collawn, James F / Bartoszewski, Rafał

European journal of cell biology

2024 Volume 103, Issue 2, Page(s) 151386

Abstract: Hypoxia-inducible factors (HIFs) are transcription factors that reprogram the transcriptome for cells to survive hypoxic insults and oxidative stress. They are important during embryonic development and reprogram the cells to utilize glycolysis when the ... ...

Abstract	Hypoxia-inducible factors (HIFs) are transcription factors that reprogram the transcriptome for cells to survive hypoxic insults and oxidative stress. They are important during embryonic development and reprogram the cells to utilize glycolysis when the oxygen levels are extremely low. This metabolic change facilitates normal cell survival as well as cancer cell survival. The key feature in survival is the transition between acute hypoxia and chronic hypoxia, and this is regulated by the transition between HIF-1 expression and HIF-2/HIF-3 expression. This transition is observed in many human cancers and endothelial cells and referred to as the HIF Switch. Here we discuss the mechanisms involved in the HIF Switch in human endothelial and cancer cells which include mRNA and protein levels of the alpha chains of the HIFs. A major continuing effort in this field is directed towards determining the differences between normal and tumor cell utilization of this important pathway, and how this could lead to potential therapeutic approaches.
Language	English
Publishing date	2024-01-20
Publishing country	Germany
Document type	Journal Article
ZDB-ID	391967-5
ISSN	1618-1298 ; 0070-2463 ; 0171-9335
ISSN (online)	1618-1298
ISSN	0070-2463 ; 0171-9335
DOI	10.1016/j.ejcb.2024.151386
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Article: Dual RNase activity of IRE1 as a target for anticancer therapies.

Bartoszewska, Sylwia / Sławski, Jakub / Collawn, James F / Bartoszewski, Rafał

Journal of cell communication and signaling

2023 Volume 17, Issue 4, Page(s) 1145–1161

Abstract: The unfolded protein response (UPR) is a cellular mechanism that protects cells during stress conditions in which there is an accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR activates three signaling pathways that function to ... ...

Abstract	The unfolded protein response (UPR) is a cellular mechanism that protects cells during stress conditions in which there is an accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR activates three signaling pathways that function to alleviate stress conditions and promote cellular homeostasis and cell survival. During unmitigated stress conditions, however, UPR activation signaling changes to promote cell death through apoptosis. Interestingly, cancer cells take advantage of this pathway to facilitate survival and avoid apoptosis even during prolonged cell stress conditions. Here, we discuss different signaling pathways associated with UPR and focus specifically on one of the ER signaling pathways activated during UPR, inositol-requiring enzyme 1α (IRE1). The rationale is that the IRE1 pathway is associated with cell fate decisions and recognized as a promising target for cancer therapeutics. Here we discuss IRE1 inhibitors and how they might prove to be an effective cancer therapeutic.
Language	English
Publishing date	2023-09-18
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2299380-0
ISSN	1873-961X ; 1873-9601
ISSN (online)	1873-961X
ISSN	1873-9601
DOI	10.1007/s12079-023-00784-5
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Article ; Online: Editorial focus: entering into the non-coding RNA era.

Bartoszewski, Rafal / Sikorski, Aleksander F

Cellular & molecular biology letters

2018 Volume 23, Page(s) 45

Abstract: Recent developments in high-throughput genotyping technologies have revealed the existence of several new classes of RNA that do not encode proteins but serve other cellular roles. To date, these non-coding RNAs (ncRNAs) have been shown to modulate both ... ...

Abstract	Recent developments in high-throughput genotyping technologies have revealed the existence of several new classes of RNA that do not encode proteins but serve other cellular roles. To date, these non-coding RNAs (ncRNAs) have been shown to modulate both gene expression and genome remodeling, thus contributing to the control of both normal and disease-related cellular processes. The attraction of this research topic can be seen in the increasing number of submissions on ncRNAs to molecular biology journals, including
MeSH term(s)	Animals ; Caenorhabditis elegans/genetics ; Gene Expression Profiling ; Humans ; Mammals/genetics ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Molecular Sequence Annotation ; RNA, Untranslated/genetics ; RNA, Untranslated/metabolism
Chemical Substances	MicroRNAs ; RNA, Untranslated
Language	English
Publishing date	2018-09-18
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2108724-6
ISSN	1689-1392 ; 1425-8153
ISSN (online)	1689-1392
ISSN	1425-8153
DOI	10.1186/s11658-018-0111-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells.

Moszyńska, Adrianna / Collawn, James F / Bartoszewski, Rafal

Biomolecules

2020 Volume 10, Issue 6

Abstract: While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less ... ...

Abstract	While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less clear. Here, we examined the effects of IRE1 on HIF-1α protein levels during hypoxia in primary human umbilical vein endothelial cells (HUVECs). The results demonstrated that HIF-1α levels peaked at 6 h of hypoxia along with two of their target genes,
MeSH term(s)	Cell Hypoxia/drug effects ; Cell Hypoxia/genetics ; Cells, Cultured ; Endoribonucleases/antagonists & inhibitors ; Endoribonucleases/metabolism ; Endoribonucleases/physiology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Gene Knockdown Techniques ; Human Umbilical Vein Endothelial Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/physiology ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/metabolism ; Protein-Serine-Threonine Kinases/physiology ; RNA, Small Interfering/pharmacology ; Signal Transduction/drug effects ; Signal Transduction/genetics
Chemical Substances	HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; RNA, Small Interfering ; ERN1 protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-)
Language	English
Publishing date	2020-06-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom10060895
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Article ; Online: The Unfolded Protein Response: A Double-Edged Sword for Brain Health

Gebert, Magdalena / Sławski, Jakub / Kalinowski, Leszek / Collawn, James F. / Bartoszewski, Rafal

Antioxidants. 2023 Aug. 21, v. 12, no. 8

2023

Abstract	Efficient brain function requires as much as 20% of the total oxygen intake to support normal neuronal cell function. This level of oxygen usage, however, leads to the generation of free radicals, and thus can lead to oxidative stress and potentially to age-related cognitive decay and even neurodegenerative diseases. The regulation of this system requires a complex monitoring network to maintain proper oxygen homeostasis. Furthermore, the high content of mitochondria in the brain has elevated glucose demands, and thus requires a normal redox balance. Maintaining this is mediated by adaptive stress response pathways that permit cells to survive oxidative stress and to minimize cellular damage. These stress pathways rely on the proper function of the endoplasmic reticulum (ER) and the activation of the unfolded protein response (UPR), a cellular pathway responsible for normal ER function and cell survival. Interestingly, the UPR has two opposing signaling pathways, one that promotes cell survival and one that induces apoptosis. In this narrative review, we discuss the opposing roles of the UPR signaling pathways and how a better understanding of these stress pathways could potentially allow for the development of effective strategies to prevent age-related cognitive decay as well as treat neurodegenerative diseases.
Keywords	apoptosis ; brain ; cell viability ; cognition ; endoplasmic reticulum ; glucose ; homeostasis ; mitochondria ; neurons ; oxidative stress ; oxygen ; stress response ; unfolded protein response
Language	English
Dates of publication	2023-0821
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12081648
Database	NAL-Catalogue (AGRICOLA)

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