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Article ; Online: Got PIDD1? Natural killer cells clear polyploid cells to ensure a balanced genome.

Brown-Suedel, Alexandra N / Bouchier-Hayes, Lisa

2023 Volume 42, Issue 20, Page(s) e115307

Abstract: Removal of polyploid cells is essential to preventing cancer and restricting tumor growth. A new study published in The EMBO Journal shows assembly of the NEMO-PIDDosome on extra centrioles. Activation of this protein complex leads to NF-κB activation ... ...

Abstract	Removal of polyploid cells is essential to preventing cancer and restricting tumor growth. A new study published in The EMBO Journal shows assembly of the NEMO-PIDDosome on extra centrioles. Activation of this protein complex leads to NF-κB activation that, in turn, induces NK cell-mediated cell clearance.
MeSH term(s)	Humans ; Gene Expression Regulation ; I-kappa B Kinase/metabolism ; Killer Cells, Natural ; NF-kappa B/metabolism ; Polyploidy ; Signal Transduction
Chemical Substances	I-kappa B Kinase (EC 2.7.11.10) ; NF-kappa B ; PIDD1 protein, human ; Pidd1 protein, mouse
Language	English
Publishing date	2023-09-11
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2023115307
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Article ; Online: The role of the nucleolus in regulating the cell cycle and the DNA damage response.

Sakthivel, Dharaniya / Brown-Suedel, Alexandra / Bouchier-Hayes, Lisa

Advances in protein chemistry and structural biology

2023 Volume 135, Page(s) 203–241

Abstract: The nucleolus has long been perceived as the site for ribosome biogenesis, but numerous studies suggest that the nucleolus carefully sequesters crucial proteins involved in multiple cellular functions. Among these, the role of nucleolus in cell cycle ... ...

Abstract	The nucleolus has long been perceived as the site for ribosome biogenesis, but numerous studies suggest that the nucleolus carefully sequesters crucial proteins involved in multiple cellular functions. Among these, the role of nucleolus in cell cycle regulation is the most evident. The nucleolus is the first responder of growth-related signals to mediate normal cell cycle progression. The nucleolus also senses different cellular stress insults by activating diverse pathways that arrest the cell cycle, promote DNA repair, or initiate apoptosis. Here, we review the emerging concepts on how the ribosomal and nonribosomal nucleolar proteins mediate such cellular effects.
MeSH term(s)	Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Cell Cycle ; Ribosomes/genetics ; Ribosomes/metabolism ; Nuclear Proteins/metabolism ; DNA Damage
Chemical Substances	Tumor Suppressor Protein p53 ; Nuclear Proteins
Language	English
Publishing date	2023-02-08
Publishing country	Netherlands
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1876-1631 ; 1876-1623
ISSN (online)	1876-1631
ISSN	1876-1623
DOI	10.1016/bs.apcsb.2023.01.001
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Article ; Online: Lethal and Non-Lethal Functions of Caspases in the DNA Damage Response.

Lopez, Karla E / Bouchier-Hayes, Lisa

Cells

2022 Volume 11, Issue 12

Abstract: Members of the caspase family are well known for their roles in the initiation and execution of cell death. Due to their function in the removal of damaged cells that could otherwise become malignant, caspases are important players in the DNA damage ... ...

Abstract	Members of the caspase family are well known for their roles in the initiation and execution of cell death. Due to their function in the removal of damaged cells that could otherwise become malignant, caspases are important players in the DNA damage response (DDR), a network of pathways that prevent genomic instability. However, emerging evidence of caspases positively or negatively impacting the accumulation of DNA damage in the absence of cell death demonstrates that caspases play a role in the DDR that is independent of their role in apoptosis. This review highlights the apoptotic and non-apoptotic roles of caspases in the DDR and how they can impact genomic stability and cancer treatment.
MeSH term(s)	Apoptosis/physiology ; Caspases/metabolism ; Cell Death ; DNA Damage ; Genomic Instability ; Humans
Chemical Substances	Caspases (EC 3.4.22.-)
Language	English
Publishing date	2022-06-10
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11121887
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Article ; Online: Cellular autophagy, an unbidden effect of caspase inhibition by zVAD-fmk.

Sakthivel, Dharaniya / Bolívar, Beatriz E / Bouchier-Hayes, Lisa

The FEBS journal

2022 Volume 289, Issue 11, Page(s) 3097–3100

Abstract: zVAD-fmk is a widely used pan-caspase inhibitor that blocks apoptosis but has undesirable side effects, including autophagy. In this issue, Needs et al. propose that zVAD-fmk induces autophagy by inhibiting the N-glycanase NGLY1 rather than caspases. ... ...

Abstract	zVAD-fmk is a widely used pan-caspase inhibitor that blocks apoptosis but has undesirable side effects, including autophagy. In this issue, Needs et al. propose that zVAD-fmk induces autophagy by inhibiting the N-glycanase NGLY1 rather than caspases. NGLY1 is essential for the ERAD response and patients with inactivating mutations in NGLY1 present with neurodevelopmental defects and organ dysfunction. The ability of NGLY1 to inhibit basal levels of autophagy may contribute to this pathology. This study demonstrates possible crosstalk between protein turnover and autophagy while also underscoring the importance of specificity when using chemical tools to interrogate these pathways. Comment on https://doi.org/10.1111/febs.16345.
MeSH term(s)	Amino Acid Chloromethyl Ketones/pharmacology ; Apoptosis ; Autophagy ; Caspase 3 ; Caspase Inhibitors/pharmacology ; Caspases/genetics ; Caspases/metabolism ; Humans
Chemical Substances	Amino Acid Chloromethyl Ketones ; Caspase Inhibitors ; Caspase 3 (EC 3.4.22.-) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2022-01-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16346
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Article ; Online: Visualization of Inflammatory Caspases Induced Proximity in Human Monocyte-Derived Macrophages.

Bolívar, Beatriz E / Bouchier-Hayes, Lisa

Journal of visualized experiments : JoVE

2022 , Issue 182

Abstract: Inflammatory caspases include caspase-1, -4, -5, -11, and -12 and belong to the subgroup of initiator caspases. Caspase-1 is required to ensure correct regulation of inflammatory signaling and is activated by proximity-induced dimerization following ... ...

Abstract	Inflammatory caspases include caspase-1, -4, -5, -11, and -12 and belong to the subgroup of initiator caspases. Caspase-1 is required to ensure correct regulation of inflammatory signaling and is activated by proximity-induced dimerization following recruitment to inflammasomes. Caspase-1 is abundant in the monocytic cell lineage and induces maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 to active secreted molecules. The other inflammatory caspases, caspase-4 and -5 (and their murine homolog caspase-11) promote IL-1β release by inducing pyroptosis. Caspase Bimolecular Fluorescence Complementation (BiFC) is a tool used to measure inflammatory caspase induced proximity as a readout of caspase activation. The caspase-1, -4, or -5 prodomain, which contains the region that binds to the inflammasome, is fused to non-fluorescent fragments of the yellow fluorescent protein Venus (Venus-N [VN] or Venus-C [VC]) that associate to reform the fluorescent Venus complex when the caspases undergo induced proximity. This protocol describes how to introduce these reporters into primary human monocyte-derived macrophages (MDM) using nucleofection, treat the cells to induce inflammatory caspase activation, and measure caspase activation using fluorescence and confocal microscopy. The advantage of this approach is that it can be used to identify the components, requirements, and localization of the inflammatory caspase activation complex in living cells. However, careful controls need to be considered to avoid compromising cell viability and behavior. This technique is a powerful tool for the analysis of dynamic caspase interactions at the inflammasome level as well as for the interrogation of the inflammatory signaling cascades in living MDM and monocytes derived from human blood samples.
MeSH term(s)	Animals ; Caspases/metabolism ; Humans ; Inflammasomes ; Macrophages/metabolism ; Mice ; Microscopy, Confocal ; Pyroptosis
Chemical Substances	Inflammasomes ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2022-04-06
Publishing country	United States
Document type	Journal Article ; Video-Audio Media ; Research Support, N.I.H., Extramural
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/63162
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Article ; Online: Targeting apoptotic caspases in cancer.

Boice, Ashley / Bouchier-Hayes, Lisa

Biochimica et biophysica acta. Molecular cell research

2020 Volume 1867, Issue 6, Page(s) 118688

Abstract: Members of the caspase family of proteases play essential roles in the initiation and execution of apoptosis. These caspases are divided into two groups: the initiator caspases (caspase-2, -8, -9 and -10), which are the first to be activated in response ... ...

Abstract	Members of the caspase family of proteases play essential roles in the initiation and execution of apoptosis. These caspases are divided into two groups: the initiator caspases (caspase-2, -8, -9 and -10), which are the first to be activated in response to a signal, and the executioner caspases (caspase-3, -6, and -7) that carry out the demolition phase of apoptosis. Many conventional cancer therapies induce apoptosis to remove the cancer cell by engaging these caspases indirectly. Newer therapeutic applications have been designed, including those that specifically activate individual caspases using gene therapy approaches and small molecules that repress natural inhibitors of caspases already present in the cell. For such approaches to have maximal clinical efficacy, emerging insights into non-apoptotic roles of these caspases need to be considered. This review will discuss the roles of caspases as safeguards against cancer in the context of the advantages and potential limitations of targeting apoptotic caspases for the treatment of cancer.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis ; Caspases/chemistry ; Caspases/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Models, Molecular ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Signal Transduction/drug effects
Chemical Substances	Antineoplastic Agents ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2020-02-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2020.118688
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Article ; Online: Lethal and Non-Lethal Functions of Caspases in the DNA Damage Response

Karla E. Lopez / Lisa Bouchier-Hayes

Cells, Vol 11, Iss 1887, p

2022 Volume 1887

Abstract	Members of the caspase family are well known for their roles in the initiation and execution of cell death. Due to their function in the removal of damaged cells that could otherwise become malignant, caspases are important players in the DNA damage response (DDR), a network of pathways that prevent genomic instability. However, emerging evidence of caspases positively or negatively impacting the accumulation of DNA damage in the absence of cell death demonstrates that caspases play a role in the DDR that is independent of their role in apoptosis. This review highlights the apoptotic and non-apoptotic roles of caspases in the DDR and how they can impact genomic stability and cancer treatment.
Keywords	caspases ; DNA damage ; genomic instability ; cell cycle ; apoptosis ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article: Caspase-2 Substrates: To Apoptosis, Cell Cycle Control, and Beyond.

Brown-Suedel, Alexandra N / Bouchier-Hayes, Lisa

Frontiers in cell and developmental biology

2020 Volume 8, Page(s) 610022

Abstract: Caspase-2 belongs to the caspase family of proteins responsible for essential cellular functions including apoptosis and inflammation. Uniquely, caspase-2 has been identified as a tumor suppressor, but how it regulates this function is still unknown. For ...

Abstract	Caspase-2 belongs to the caspase family of proteins responsible for essential cellular functions including apoptosis and inflammation. Uniquely, caspase-2 has been identified as a tumor suppressor, but how it regulates this function is still unknown. For many years, caspase-2 has been considered an "orphan" caspase because, although it is able to induce apoptosis, there is an abundance of conflicting evidence that questions its necessity for apoptosis. Recent evidence supports that caspase-2 has non-apoptotic functions in the cell cycle and protection from genomic instability. It is unclear how caspase-2 regulates these opposing functions, which has made the mechanism of tumor suppression by caspase-2 difficult to determine. As a protease, caspase-2 likely exerts its functions by proteolytic cleavage of cellular substrates. This review highlights the known substrates of caspase-2 with a special focus on their functional relevance to caspase-2's role as a tumor suppressor.
Language	English
Publishing date	2020-12-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2020.610022
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Article ; Online: The NLRP3 inflammasome fires up heme-induced inflammation in hemolytic conditions.

Salgar, Suruchi / Bolívar, Beatriz E / Flanagan, Jonathan M / Anum, Shaniqua J / Bouchier-Hayes, Lisa

Translational research : the journal of laboratory and clinical medicine

2022 Volume 252, Page(s) 34–44

Abstract: Overactive inflammatory responses are central to the pathophysiology of many hemolytic conditions including sickle cell disease. Excessive hemolysis leads to elevated serum levels of heme due to saturation of heme scavenging mechanisms. Extracellular ... ...

Abstract	Overactive inflammatory responses are central to the pathophysiology of many hemolytic conditions including sickle cell disease. Excessive hemolysis leads to elevated serum levels of heme due to saturation of heme scavenging mechanisms. Extracellular heme has been shown to activate the NLRP3 inflammasome, leading to activation of caspase-1 and release of pro-inflammatory cytokines IL-1β and IL-18. Heme also activates the non-canonical inflammasome pathway, which may contribute to NLRP3 inflammasome formation and leads to pyroptosis, a type of inflammatory cell death. Some clinical studies indicate there is a benefit to blocking the NLRP3 inflammasome pathway in patients with sickle cell disease and other hemolytic conditions. However, a thorough understanding of the mechanisms of heme-induced inflammasome activation is needed to fully leverage this pathway for clinical benefit. This review will explore the mechanisms of heme-induced NLRP3 inflammasome activation and the role of this pathway in hemolytic conditions including sickle cell disease.
MeSH term(s)	Humans ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Heme/metabolism ; Hemolysis ; Inflammation/metabolism ; Anemia, Sickle Cell/complications ; Interleukin-1beta
Chemical Substances	Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; Heme (42VZT0U6YR) ; Interleukin-1beta
Language	English
Publishing date	2022-08-28
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2246684-8
ISSN	1878-1810 ; 1532-6543 ; 1931-5244
ISSN (online)	1878-1810 ; 1532-6543
ISSN	1931-5244
DOI	10.1016/j.trsl.2022.08.011
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Article ; Online: The nucleolus: A new home for the PIDDosome.

Bouchier-Hayes, Lisa / Sidi, Samuel

Cell cycle (Georgetown, Tex.)

2017 Volume 16, Issue 17, Page(s) 1562–1563

MeSH term(s)	Caspase 2 ; Cell Nucleolus ; Nuclear Proteins
Chemical Substances	Nuclear Proteins ; Caspase 2 (EC 3.4.22.-)
Language	English
Publishing date	2017-07-27
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2017.1355179
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