scholarly journals The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 159-176
Author(s):  
Richard J. Epstein
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Inflammatory Responses ◽  
Inducible Promoter ◽  
Loss Of Function ◽  
Coding Region ◽  
Antiinflammatory Drugs ◽  
Reading Frame ◽  
Secret Identities

The human TMPRSS2 gene is pathogenetically implicated in both coronaviral lung infection and prostate cancer, suggesting its potential as a drug target in both contexts. SARS-COV-2 spike polypeptides are primed by the host transmembrane TMPRSS2 protease, triggering virus fusion with epithelial cell membranes followed by an endocytotic internalisation process that bypasses normal endosomal activation of cathepsin-mediated innate immunity; viral co-opting of TMPRSS2 thus favors microbial survivability by attenuating host inflammatory responses. In contrast, most early hormone-dependent prostate cancers express TMPRSS2:ERG fusion genes arising from deletions that eliminate the TMPRSS2 coding region while juxtaposing its androgen-inducible promoter and the open reading frame of ERG, upregulating pro-inflammatory ERG while functionally disabling TMPRSS2. Moreover, inflammatory oxidative DNA damage selects for TMPRSS2:ERG-fused cancers, whereas patients treated with antiinflammatory drugs develop fewer of these fusion-dependent tumors. These findings imply that TMPRSS2 protects the prostate by enabling endosomal bypass of pathogens which could otherwise trigger inflammation-induced DNA damage that predisposes to TMPRSS2:ERG fusions. Hence, the high oncogenic selectability of TMPRSS2:ERG fusions may reflect a unique pro-inflammatory synergy between androgenic ERG gain-of-function and fusogenic TMPRSS2 loss-of-function, cautioning against the use of TMPRSS2-inhibitory drugs to prevent or treat early prostate cancer.

Oxidative DNA damage and inflammatory responses in cultured human cells and in humans exposed to traffic-related particles

2014 ◽  
Vol 217 (1) ◽  
pp. 23-33 ◽  
Author(s):  
Udomratana Vattanasit ◽  
Panida Navasumrit ◽  
Man Bahadur Khadka ◽  
Jantamas Kanitwithayanun ◽  
Jeerawan Promvijit ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Inflammatory Responses ◽  
Human Cells ◽  
Cultured Human Cells

Oxidative DNA damage and inflammatory responses in children exposed to arsenic in utero and during early childhood

2016 ◽  
Vol 259 ◽  
pp. S116
Author(s):  
P. Navasumrit ◽  
K. Chaisatra ◽  
P. Hunsonthi ◽  
P. Hinhumpatch ◽  
P. Phukphan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Early Childhood ◽  
Oxidative Dna Damage ◽  
Inflammatory Responses ◽  
In Utero

scholarly journals Oxidative DNA Damage in the Prostate May Predispose Men to a Higher Risk of Prostate Cancer

2009 ◽  
Vol 2 (1) ◽  
pp. 39-45 ◽  
Author(s):  
Jennifer D. Wu ◽  
Daniel W. Lin ◽  
Stephanie T. Page ◽  
Ashley D. Lundgren ◽  
Lawrence D. True ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Oxidative Dna Damage

scholarly journals Oxidative DNA Damage in Prostate Cancer Patients Consuming Tomato Sauce-Based Entrees as a Whole-Food Intervention

2001 ◽  
Vol 93 (24) ◽  
pp. 1872-1879 ◽  
Author(s):  
L. Chen ◽  
M. Stacewicz-Sapuntzakis ◽  
C. Duncan ◽  
R. Sharifi ◽  
L. Ghosh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cancer Patients ◽  
Oxidative Dna Damage ◽  
Tomato Sauce

scholarly journals Genetically-induced Redox Stress Occurs in a Yeast Model for Roberts Syndrome

2021 ◽  
Author(s):  
Michael G Mfarej ◽  
Robert V Skibbens
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Gene Mutations ◽  
Loss Of Function ◽  
Redox Stress ◽  
Cellular Processes ◽  
Transcriptional Dysregulation ◽  
Dna Damaging Agents ◽  
Roberts Syndrome ◽  
Mutant Cells

Abstract Roberts Syndrome (RBS) is a multi-spectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities and often intellectual disabilities. The genetic basis of RBS is rooted in loss-of-function mutations in the essential N-acetyltransferase ESCO2 which is conserved from yeast (Eco1/Ctf7) to humans. ESCO2/Eco1 regulate many cellular processes that impact chromatin structure, chromosome transmission, gene expression, and repair of the genome. The etiology of RBS remains contentious with current models that include transcriptional dysregulation or mitotic failure. Here, we report evidence that supports an emerging model rooted in defective DNA damage responses. First, the results reveal that redox stress is elevated in both eco1 and cohesion factor Saccharomyces cerevisiae mutant cells. Second, we provide evidence that Eco1 and cohesion factors are required for the repair of oxidative DNA damage such that ECO1 and cohesin gene mutations result in reduced cell viability and hyperactivation of DNA damage checkpoints that occur in response to oxidative stress. Moreover, we show that mutation of ECO1 is solely sufficient to induce endogenous redox stress and sensitizes mutant cells to exogenous genotoxic challenges. Remarkably, antioxidant treatment desensitizes eco1 mutant cells to a range of DNA damaging agents, raising the possibility that modulating the cellular redox state may represent an important avenue of treatment for Roberts Syndrome and tumors that bear ESCO2 mutations.

scholarly journals MicroRNAs Modulate Oxidative Stress in Hypertension through PARP-1 Regulation

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Douglas F. Dluzen ◽  
Yoonseo Kim ◽  
Paul Bastian ◽  
Yongqing Zhang ◽  
Elin Lehrmann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Survival ◽  
Oxidative Dna Damage ◽  
White Women ◽  
Luciferase Reporter ◽  
Coding Region ◽  
Age Related ◽  
Parp 1

Oxidative stress is thought to contribute to aging and age-related diseases, such as cardiovascular and neurodegenerative diseases, and is a risk factor for systemic arterial hypertension. Previously, we reported differential mRNA and microRNA (miRNA) expression between African American (AA) and white women with hypertension. Here, we found that the poly-(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein involved in DNA repair and other cellular processes, is upregulated in AA women with hypertension. To explore this mechanism, we identified two miRNAs, miR-103a-2-5p and miR-585-5p, that are differentially expressed with hypertension and were predicted to target PARP1. Through overexpression of each miRNA-downregulated PARP-1 mRNA and protein levels and using heterologous luciferase reporter assays, we demonstrate that miR-103a-2-5p and miR-585-5p regulate PARP1 through binding within the coding region. Given the important role of PARP-1 in DNA repair, we assessed whether overexpression of miR-103a-2-5p or miR-585-5p affected DNA damage and cell survival. Overexpression of these miRNAs enhanced DNA damage and decreased both cell survival and colony formation. These findings highlight the role for PARP-1 in regulating oxidative DNA damage in hypertension and identify important new miRNA regulators of PARP-1 expression. These insights may provide additional avenues to understand hypertension health disparities.

scholarly journals Molecular characterization of cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) associated with the erythrocyte antigens in dogs

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Yumiko Uno ◽  
Shota Kawakami ◽  
Kazuhiko Ochiai ◽  
Toshinori Omi
Keyword(s):  
Point Mutations ◽  
Pcr Analysis ◽  
Blood Group System ◽  
Nucleotide Polymorphisms ◽  
Loss Of Function ◽  
Coding Region ◽  
Essential Information ◽  
Reading Frame ◽  
Acetylneuraminic Acid ◽  
Exonic Snps

Abstract Background N-glycolylneuraminic acid (Neu5Gc) is synthesized from its precursor N-acetylneuraminic acid (Neu5Ac) by cytidine-5′-monophospho-N acetylneuraminic acid hydroxylase (CMAH), which is encoded by the CMAH gene. Most mammals have both Neu5Gc and Neu5Ac, but humans and ferrets have only Neu5Ac because of loss-of-function mutations. Dogs and cats are polymorphic for Neu5Gc and Neu5Ac expression like cats, in which the CMAH gene is responsible for the AB Blood group system. Although the CMAH gene has been characterized in many species, not much is known about it in dogs. In this study, we cloned the dog CMAH cDNA, and performed mRNA expression analysis of this gene in several organs. We also identified single nucleotide polymorphisms (SNPs) in the CMAH gene. Results We cloned the 1737-bp open reading frame of the dog CMAH gene. This gene consists of at least 14 coding exons and codes for a polypeptide of 578 amino acids and is located on chromosome 35. The amino acid identities of dog CMAH with the corresponding sequences from cat, pig, chimpanzee, mouse, and rat were high (89 to 93%). RT-PCR analysis showed that the dog CMAH cDNA was expressed in various tissues. We identified four exonic SNPs (three synonymous and one non-synonymous), 11 intronic SNPs, and an indel in 11 dog breeds by analyzing the nucleotide sequences of the 14 exons, including the coding region of CMAH. In the genotype of the non-synonymous SNP, c.554 A > G (p.Lys185Arg), in a total of 285 dogs of seven different breeds, the allele G was widely distributed, and the allele A was the most frequent in the Shiba dogs. The dogs expressing Neu5Ac did not carry the loss-of-function deletion of CMAH found in humans and ferrets, and it remains unclear whether the point mutations influence the expression of Neu5Ac. Conclusions We characterized the canine CMAH gene at the molecular level for the first time. The results obtained in this study provide essential information that will help in understanding the molecular roles of the CMAH gene in canine erythrocyte antigens.

OXIDATIVE DNA DAMAGE IN PATIENTS WITH PROSTATE CANCER AND ITS RESPONSE TO TREATMENT

2004 ◽  
Vol 171 (4) ◽  
pp. 1533-1536 ◽  
Author(s):  
HIDEAKI MIYAKE ◽  
ISAO HARA ◽  
SADAO KAMIDONO ◽  
HIROSHI ETO
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Response To Treatment

scholarly journals Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Laura Marruecos ◽  
Joan Manils ◽  
Cristina Moreta ◽  
Diana Gómez ◽  
Ingrid Filgaira ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Genome Stability ◽  
Oxidative Dna Damage ◽  
Inflammatory Responses ◽  
Interleukin 12 ◽  
Allele Loss ◽  
Inflammatory Status ◽  
Differential Increase ◽  
Over Time

AbstractDose of Trp53, the main keeper of genome stability, influences tumorigenesis; however, the causes underlying and driving tumorigenesis over time by the loss of a single p53 allele are still poorly characterized. Here, we found that single p53 allele loss specifically impacted the oxidative, DNA damage and inflammatory status of hematopoietic lineages. In particular, single Trp53 allele loss in mice triggered oxidative stress in peripheral blood granulocytes and spleenocytes, whereas lack of two Trp53 alleles produced enhanced oxidative stress in thymus cells, resulting in a higher incidence of lymphomas in the Trp53 knockout (KO) mice compared with hemizygous (HEM). In addition, single or complete loss of Trp53 alleles, as well as p53 downregulation, led to a differential increase in basal, LPS- and UVB-induced expression of a plethora of pro-inflammatory cytokine, such as interleukin-12 (Il-12a), TNFα (Tnfa) and interleukin (Il-23a) in bone marrow-derived macrophage cells (BMDMs) compared to WT cells. Interestingly, p53-dependent increased inflammatory gene expression correlated with deregulated expression of the NF-κB pathway inhibitor IκBα. Chromatin immunoprecipitation data revealed decreased p65 binding to Nfkbia in the absence of p53 and p53 binding to Nfkbia promoter, uncovering a novel crosstalk mechanism between p53 and NF-κB transcription factors. Overall, our data suggest that single Trp53 allele loss can drive a sustained inflammatory, DNA damage and oxidative stress response that, over time, facilitate and support carcinogenesis.

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