scholarly journals Caspase-14—From Biomolecular Basics to Clinical Approach. A Review of Available Data

2021 ◽  
Vol 22 (11) ◽  
pp. 5575
Author(s):  
Agnieszka Markiewicz ◽  
Dawid Sigorski ◽  
Mateusz Markiewicz ◽  
Agnieszka Owczarczyk-Saczonek ◽  
Waldemar Placek
Keyword(s):  
Cell Death ◽  
Physiological Role ◽  
Skin Barrier ◽  
Clinical Aspects ◽  
Clinical Approach ◽  
Search Term ◽  
Caspase Family ◽  
Skin Conditions ◽  
Theoretical Science

Caspase-14 is a unique member of the caspase family—a family of molecules participating in apoptosis. However, it does not affect this process but regulates another form of programmed cell death—cornification, which is characteristic of the epidermis. Therefore, it plays a crucial role in the formation of the skin barrier. The cell death cycle has been a subject of interest for researchers for decades, so a lot of research has been done to expand the understanding of caspase-14, its role in cell homeostasis and processes affecting its expression and activation. Conversely, it is also an interesting target for clinical researchers searching for its role in the physiology of healthy individuals and its pathophysiology in particular diseases. A summary was done in 2008 by Denecker et al., concentrating mostly on the biotechnological aspects of the molecule and its physiological role. However, a lot of new data have been reported, and some more practical and clinical research has been conducted since then. The majority of studies tackled the issue of clinical data presenting the role of caspase in the etiopathology of many diseases such as retinal dysfunctions, multiple malignancies, and skin conditions. This review summarizes the available knowledge on the molecular and, more interestingly, the clinical aspects of caspase-14. It also presents how theoretical science may pave the way for medical research. Methods: The authors analyzed publications available on PubMed until 21 March 2021, using the search term “caspase 14”.

scholarly journals Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis

2007 ◽  
Vol 179 (2) ◽  
pp. 255-267 ◽  
Author(s):  
Karthik Jeganathan ◽  
Liviu Malureanu ◽  
Darren J. Baker ◽  
Susan C. Abraham ◽  
Jan M. van Deursen
Keyword(s):  
Cell Death ◽  
Chromosome Segregation ◽  
Physiological Role ◽  
Mitotic Checkpoint ◽  
Critical Threshold ◽  
Wild Type ◽  
Checkpoint Protein ◽  
Chromosome Missegregation ◽  
Mitotic Checkpoint Protein

The physiological role of the mitotic checkpoint protein Bub1 is unknown. To study this role, we generated a series of mutant mice with a gradient of reduced Bub1 expression using wild-type, hypomorphic, and knockout alleles. Bub1 hypomorphic mice are viable, fertile, and overtly normal despite weakened mitotic checkpoint activity and high percentages of aneuploid cells. Bub1 haploinsufficient mice, which have a milder reduction in Bub1 protein than Bub1 hypomorphic mice, also exhibit reduced checkpoint activity and increased aneuploidy, but to a lesser extent. Although cells from Bub1 hypomorphic and haploinsufficient mice have similar rates of chromosome missegregation, cell death after an aberrant separation decreases dramatically with declining Bub1 levels. Importantly, Bub1 hypomorphic mice are highly susceptible to spontaneous tumors, whereas Bub1 haploinsufficient mice are not. These findings demonstrate that loss of Bub1 below a critical threshold drives spontaneous tumorigenesis and suggest that in addition to ensuring proper chromosome segregation, Bub1 is important for mediating cell death when chromosomes missegregate.

scholarly journals Expression of a Mitochondrial Peroxiredoxin Prevents Programmed Cell Death in Leishmania donovani

2006 ◽  
Vol 5 (5) ◽  
pp. 861-870 ◽  
Author(s):  
Simone Harder ◽  
Meike Bente ◽  
Kerstin Isermann ◽  
Iris Bruchhaus
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Mitochondrial Membrane ◽  
Leishmania Donovani ◽  
Physiological Role ◽  
Logarithmic Phase ◽  
Insect Vector ◽  
Oxygen Species ◽  
Late Logarithmic Phase

ABSTRACT Leishmania promastigote cells transmitted by the insect vector get phagocytosed by macrophages and convert into the amastigote form. During development and transformation, the parasites are exposed to various concentrations of reactive oxygen species, which can induce programmed cell death (PCD). We show that a mitochondrial peroxiredoxin (LdmPrx) protects Leishmania donovani from PCD. Whereas this peroxiredoxin is restricted to the kinetoplast area in promastigotes, it covers the entire mitochondrion in amastigotes, accompanied by dramatically increased expression. A similar change in the expression pattern was observed during the growth of Leishmania from the early to the late logarithmic phase. Recombinant LdmPrx shows typical peroxiredoxin-like enzyme activity. It is able to detoxify organic and inorganic peroxides and prevents DNA from hydroxyl radical-induced damage. Most notably, Leishmania parasites overexpressing this peroxiredoxin are protected from hydrogen peroxide-induced PCD. This protection is also seen in promastigotes grown to the late logarithmic phase, also characterized by high expression of this peroxiredoxin. Apparently, the physiological role of this peroxiredoxin is stabilization of the mitochondrial membrane potential and, as a consequence, inhibition of PCD through removal of peroxides.

scholarly journals OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer

2019 ◽  
Author(s):  
Rune Busk Damgaard ◽  
Helen E. Jolin ◽  
Michael E.D. Allison ◽  
Susan E. Davies ◽  
Andrew N.J. McKenzie ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Liver Disease ◽  
Physiological Role ◽  
Malignant Tumours ◽  
Malignant Growth ◽  
Mtor Inhibition ◽  
Polyubiquitin Chains ◽  
Apoptosis And Inflammation

SummaryThe deubiquitinase OTULIN removes methionine-1 (M1)-linked polyubiquitin chains to regulate TNF-mediated inflammation and cell death, but the physiological role of OTULIN outside the immune system is poorly understood. Here, we identify OTULIN as a liver tumour suppressor in mice. Hepatocyte-specific OTULIN deletion causes spontaneous steatohepatitis, extensive fibrosis, and pre-malignant tumours by eight weeks of age, which progresses to hepatocellular carcinoma by 7-12 months. OTULIN deficiency triggers apoptosis and inflammation in the liver, but surprisingly, steatohepatitis and pre-malignant growth is independent of TNFR1 signalling. Instead, the pathology in OTULIN-deficient livers is associated with increased mTOR activation, and mTOR inhibition with rapamycin reduces fibrosis and pre-malignant growth. This demonstrates that OTULIN is critical for maintaining liver homeostasis and preventing mTOR-driven liver disease.

scholarly journals The Immunological Impact of IL-1 Family Cytokines on the Epidermal Barrier

2021 ◽  
Vol 12 ◽  
Author(s):  
Tom Macleod ◽  
Anna Berekmeri ◽  
Charlie Bridgewood ◽  
Martin Stacey ◽  
Dennis McGonagle ◽  
...  
Keyword(s):  
Barrier Function ◽  
Family Members ◽  
Physiological Role ◽  
Skin Barrier ◽  
Skin Barrier Function ◽  
Inhibitory Pathway ◽  
Gain Of Function ◽  
Cutaneous Inflammation ◽  
Epidermal Barrier

The skin barrier would not function without IL-1 family members, but their physiological role in the immunological aspects of skin barrier function are often overlooked. This review summarises the role of IL-1 family cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37 and IL-38) in the skin. We focus on novel aspects of their interaction with commensals and pathogens, the important impact of proteases on cytokine activity, on healing responses and inflammation limiting mechanisms. We discuss IL-1 family cytokines in the context of IL-4/IL-13 and IL-23/IL-17 axis-driven diseases and highlight consequences of human loss/gain of function mutations in activating or inhibitory pathway molecules. This review highlights recent findings that emphasize the importance of IL-1 family cytokines in both physiological and pathological cutaneous inflammation and emergent translational therapeutics that are helping further elucidate these cytokines.

scholarly journals Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction

2006 ◽  
Vol 203 (13) ◽  
pp. 2939-2951 ◽  
Author(s):  
Miriam Erlacher ◽  
Verena Labi ◽  
Claudia Manzl ◽  
Günther Böck ◽  
Alexandar Tzankov ◽  
...  
Keyword(s):  
Cell Death ◽  
Physiological Role ◽  
B Cell Lymphoma ◽  
Apoptosis Induction ◽  
Induced Apoptosis ◽  
The Individual ◽  
Rate Limiting ◽  
Lymphatic Organs ◽  
Single Knockout

The physiological role of B cell lymphoma 2 (Bcl-2) homology 3–only proteins has been investigated in mice lacking the individual genes identifying rate-limiting roles for Bim (Bcl-2–interacting mediator of cell death) and Puma (p53–up-regulated modulator of apoptosis) in apoptosis induction. The loss of Bim protects lymphocytes from apoptosis induced by cytokine deprivation and deregulated Ca++ flux and interferes with the deletion of autoreactive lymphocytes and the shutdown of immune responses. In contrast, Puma is considered the key mediator of p53-induced apoptosis. To investigate the hypothesis that Bim and Puma have overlapping functions, we generated mice lacking both genes and found that bim−/−/puma−/− animals develop multiple postnatal defects that are not observed in the single knockout mice. Most strikingly, hyperplasia of lymphatic organs is comparable with that observed in mice overexpressing Bcl-2 in all hemopoietic cells exceeding the hyperplasia observed in bim−/− mice. Bim and Puma also have clearly overlapping functions in p53-dependent and -independent apoptosis. Their combined loss promotes spontaneous tumorigenesis, causing the malignancies observed in Bcl-2 transgenic mice, but does not exacerbate the autoimmunity observed in the absence of Bim.

scholarly journals Spleen-Dependent Turnover of CD11b Peripheral Blood B Lymphocytes in Bovine Leukemia Virus-Infected Sheep

2006 ◽  
Vol 80 (24) ◽  
pp. 11998-12008 ◽  
Author(s):  
Arnaud Florins ◽  
Nicolas Gillet ◽  
Becca Asquith ◽  
Christophe Debacq ◽  
Geneviève Jean ◽  
...  
Keyword(s):  
Cell Death ◽  
B Lymphocytes ◽  
Peripheral Blood ◽  
Bovine Leukemia Virus ◽  
Leukemia Virus ◽  
Physiological Role ◽  
Infected Sheep ◽  
Lymphoid Tissues

ABSTRACT Lymphocyte homeostasis is determined by a critical balance between cell proliferation and death, an equilibrium which is deregulated in bovine leukemia virus (BLV)-infected sheep. We have previously shown that an excess of proliferation occurs in lymphoid tissues and that the peripheral blood population is prone to increased cell death. To further understand the mechanisms involved, we evaluated the physiological role of the spleen in this accelerated turnover. To this end, B lymphocytes were labeled in vivo using a fluorescent marker (carboxyfluorescein diacetate succinimidyl ester), and the cell kinetic parameters (proliferation and death rates) of animals before and after splenectomy were compared. We show that the enhanced cell death observed in BLV-infected sheep is abrogated after splenectomy, revealing a key role of the spleen in B-lymphocyte dynamics.

scholarly journals Expression, activation, and role of AKT isoforms in the uterus

Reproduction ◽  
2014 ◽  
Vol 148 (5) ◽  
pp. R85-R95 ◽  
Author(s):  
François Fabi ◽  
Eric Asselin
Keyword(s):  
Cell Death ◽  
Endometrial Cancer ◽  
Embryo Implantation ◽  
Physiological Role ◽  
Molecular Processes ◽  
Cellular Processes ◽  
Akt Isoforms ◽  
High Level ◽  
Reproductive Processes

The three isoforms of AKT: AKT1, AKT2, and AKT3, are crucial regulators of both normal and pathological cellular processes. Each of these isoforms exhibits a high level of homology and functional redundancy with each other. However, while being highly similar and structurally homologous, a rising amount of evidence is showing that each isoform possesses specific targets as well as preferential subcellular localization. The role of AKT has been studied extensively in reproductive processes, but isoform-specific roles are yet to be fully understood. This review will focus on the role of AKT in the uterus and its function in processes related to cell death and proliferation such as embryo implantation, decidualization, endometriosis, and endometrial cancer in an isoform-centric manner. In this review, we will cover the activation of AKT in various settings, localization of isoforms in subcellular compartments, and the effect of isoform expression on cellular processes. To fully understand the dynamic molecular processes taking place in the uterus, it is crucial that we better understand the physiological role of AKT isoforms as well as their function in the emergence of diseases.

Requirement of neurotrophin-3 for the survival of proliferating trigeminal ganglion progenitor cells

Development ◽  
1996 ◽  
Vol 122 (8) ◽  
pp. 2405-2414 ◽  
Author(s):  
W.M. elshamy ◽  
P. Ernfors
Keyword(s):  
Cell Death ◽  
Progenitor Cells ◽  
Trigeminal Ganglion ◽  
Physiological Role ◽  
Proliferating Cells ◽  
Neurotrophin 3 ◽  
Dividing Cells ◽  
Incorporated Brdu ◽  
Ganglion Neurons

The aim of this study was to identify the physiological role of neurotrophin-3 (NT-3) in the development of trigeminal ganglion sensory neurons. For this purpose we have analysed mice carrying a deletion in the NT-3 gene (NT-3−/− mice). In these mice, by embryonic day (E) 11.25% of the trigeminal ganglion neurons were absent and one day later, approximately 50% were absent, after which no further significant changes were observed. Mice carrying one functional NT-3 gene (NT-3+/− mice) displayed a less severe deficit than that of NT-3−/− mice. Whereas programmed cell death occurred between E12 and E14 in the control mice, pronounced excessive cell death was apparent prior to this in the NT-3−/− mice. The excessive cell death led to a progressive decline in the number of proliferating cells without a significant change in the fraction of dividing cells and total number of neurons, indicating that the neuronal deficit of NT-3−/− mice was caused by cell death of trigeminal ganglion progenitors. Furthermore, the degenerating cells had incorporated BrdU, a nucleotide analogue which labels proliferating cells, and expressed nestin, a marker for progenitor cells. Only rarely were degenerating cells seen to express peripherin, present in postmitotic neurons. These data provide evidence that NT-3 is a survival factor for trigeminal ganglion progenitor cells, and suggests that limiting amounts of NT-3 could influence progenitor cell numbers during gangliogenesis.

scholarly journals Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment

2009 ◽  
Vol 187 (7) ◽  
pp. 1037-1054 ◽  
Author(s):  
Peter Geserick ◽  
Mike Hupe ◽  
Maryline Moulin ◽  
W. Wei-Lynn Wong ◽  
Maria Feoktistova ◽  
...  
Keyword(s):  
Cell Death ◽  
Death Receptor ◽  
Physiological Role ◽  
Inhibitory Protein ◽  
Interacting Protein ◽  
Complex Ii ◽  
Signaling Complex ◽  
Iap Antagonist ◽  
Cellular Inhibitors

A role for cellular inhibitors of apoptosis (IAPs [cIAPs]) in preventing CD95 death has been suspected but not previously explained mechanistically. In this study, we find that the loss of cIAPs leads to a dramatic sensitization to CD95 ligand (CD95L) killing. Surprisingly, this form of cell death can only be blocked by a combination of RIP1 (receptor-interacting protein 1) kinase and caspase inhibitors. Consistently, we detect a large increase in RIP1 levels in the CD95 death-inducing signaling complex (DISC) and in a secondary cytoplasmic complex (complex II) in the presence of IAP antagonists and loss of RIP1-protected cells from CD95L/IAP antagonist–induced death. Cells resistant to CD95L/IAP antagonist treatment could be sensitized by short hairpin RNA–mediated knockdown of cellular FLICE-inhibitory protein (cFLIP). However, only cFLIPL and not cFLIPS interfered with RIP1 recruitment to the DISC and complex II and protected cells from death. These results demonstrate a fundamental role for RIP1 in CD95 signaling and provide support for a physiological role of caspase-independent death receptor–mediated cell death.

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