CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution

AbstractAntagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca2+ and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates.

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CaMKII oxidation is a performance/disease trade-off in vertebrate evolution

10.1101/767525 ◽

2019 ◽

Cited By ~ 1

Author(s):

Qinchuan Wang ◽

Erick O. Hernández-Ochoa ◽

Meera C. Viswanathan ◽

Ian D. Blum ◽

Jonathan M. Granger ◽

...

Keyword(s):

Comparative Genomic ◽

Behavioural Ecology ◽

Oxygen Species ◽

Trade Off ◽

Stem Lineage ◽

Intracellular Ca ◽

Health And Disease ◽

Evolutionary Success ◽

Improved Performance ◽

Camkii Activation

Reactive oxygen species (ROS) contribute to health and disease. CaMKII is a widely expressed enzyme whose activation by oxidation of regulatory domain methionines (ox-CaMKII) contributes to cardiovascular disease, asthma, and cancer. Here we integrate comparative genomic and experimental data to show that CaMKII activation by ROS arose more than half-a-billion years ago on the vertebrate stem lineage where it constituted a bridge between ROS and increased intracellular Ca2+ release, exercise responsive gene transcription, and improved performance in skeletal muscle. These enhancements to fight-or-flight physiology were likely key in facilitating a well-evidenced shift in the behavioural ecology of our immediate chordate ancestors, and, in turn, the evolutionary success of vertebrates. Still, the ox-CaMKII innovation for augmenting performance must be considered a critical evolutionary trade-off, as it rendered us more susceptible to common and often fatal diseases linked to excessive ROS.

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The potential role of STAT3 In the APE1/NF-kB regulatory axis in K-rasLSL.G12D/+;Pdx-1-Cre (KC) pancreatic tumor model

Proceedings of IMPRS ◽

10.18060/25948 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Eyram Kpenu ◽

Mark Kelley

Keyword(s):

Tumor Cells ◽

Cell Lines ◽

Pancreatic Tumor ◽

Tumor Model ◽

Redox Signaling ◽

Genetically Engineered ◽

Multifunctional Protein ◽

Enhanced Sensitivity ◽

Genetically Engineered Mice

APE1/Ref-1 (apurinic/apyrimidinic endonuclease-redox effector factor 1) is a multifunctional protein that has been shown to be overexpressed in multiple types of cancer. The overexpression of APE1/Ref-1 is linked to higher cancer cell survival and increased patient mortality. Furthermore, APE1/Ref-1 is a key regulator of transcription factors (TF) through redox signaling and protein-protein interaction. It is involved in proliferative and inflammatory signaling upregulated in cancer. Transcription factor NF-kB is involved in inflammatory cytokine expression and has been shown to be regulated by Ref-1. My project investigated how Ref-1 regulates NF-kB, specifically Rel-A, in a model using K-rasLSL.G12D/+; Pdx-1-Cre (KC) pancreatic tumor cells (KC3590) derived from genetically engineered mice. Additionally, I explored other TFs within the APE1/Ref-1 signaling pathway, such as STAT3, in this model. My work involved knocking down STAT3 levels within four variations of the KC3590 line. These were the KC3590/ΔNF-kB (parent) and KC3590/ΔNF-kB vector lines (vector) which contain exon deletions within the NF-kB gene rendering it nonfunctional. KC3590/13 and KC3590/15 are cell lines which are KC3590/ΔNF-B cells with functional full-length NF-kB added to the cells. Previous experiments demonstrated that the ΔNF-kB and ΔNF-kB vector lines are resistant to treatment by the specific Ref-1 inhibitors, including APX3330, which inhibit the redox signaling function of Ref-1. Initial data demonstrated that adding back functional NF-kB to the NF-kB deficient cells reestablished sensitivity to APX3330, presumably due to the reintroduction of the Ref-1 target, NF-kB. Knockdown of STAT3 expression in the ΔNF-kB and ΔNF-kB vector lines demonstrated some sensitivity to APX3330, however, in the C13/15 cell lines, no enhanced sensitivity was observed. These data support the hypothesis that NF-kB is the major TF driving the growth of KC pancreatic tumor cells. Subsequent studies will clarify further the role of APE1/Ref-1 regulation in the KC model and the relative importance of APE1/Ref-1’s target TFs.

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Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells

Nature Communications ◽

10.1038/ncomms1395 ◽

2011 ◽

Vol 2 (1) ◽

Cited By ~ 60

Author(s):

Monika Raab ◽

Sven Kappel ◽

Andrea Krämer ◽

Mourad Sanhaji ◽

Yves Matthess ◽

...

Keyword(s):

Targeted Therapies ◽

Mammalian Cells ◽

Genetically Engineered ◽

Genetically Engineered Mice

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Tenascin-C in Heart Diseases—The Role of Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms22115828 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5828

Author(s):

Kyoko Imanaka-Yoshida

Keyword(s):

Ventricular Remodeling ◽

Heart Diseases ◽

Genetically Engineered ◽

Matricellular Protein ◽

Myocardial Repair ◽

Inflammatory Reactions ◽

Tenascin C ◽

Genetically Engineered Mice

Tenascin-C (TNC) is a large extracellular matrix (ECM) glycoprotein and an original member of the matricellular protein family. TNC is transiently expressed in the heart during embryonic development, but is rarely detected in normal adults; however, its expression is strongly up-regulated with inflammation. Although neither TNC-knockout nor -overexpressing mice show a distinct phenotype, disease models using genetically engineered mice combined with in vitro experiments have revealed multiple significant roles for TNC in responses to injury and myocardial repair, particularly in the regulation of inflammation. In most cases, TNC appears to deteriorate adverse ventricular remodeling by aggravating inflammation/fibrosis. Furthermore, accumulating clinical evidence has shown that high TNC levels predict adverse ventricular remodeling and a poor prognosis in patients with various heart diseases. Since the importance of inflammation has attracted attention in the pathophysiology of heart diseases, this review will focus on the roles of TNC in various types of inflammatory reactions, such as myocardial infarction, hypertensive fibrosis, myocarditis caused by viral infection or autoimmunity, and dilated cardiomyopathy. The utility of TNC as a biomarker for the stratification of myocardial disease conditions and the selection of appropriate therapies will also be discussed from a clinical viewpoint.

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Characterization and visualization of murine coagulation factor VIII-producing cells in vivo

Scientific Reports ◽

10.1038/s41598-021-94307-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Morisada Hayakawa ◽

Asuka Sakata ◽

Hiroko Hayakawa ◽

Hikari Matsumoto ◽

Takafumi Hiramoto ◽

...

Keyword(s):

Endothelial Cells ◽

Factor Viii ◽

Fluorescent Protein ◽

Coagulation Factor ◽

Coagulation Factors ◽

Genetically Engineered ◽

Coagulation Factor Viii ◽

Liver Sinusoidal Endothelial Cells ◽

Genetically Engineered Mice

AbstractCoagulation factors are produced from hepatocytes, whereas production of coagulation factor VIII (FVIII) from primary tissues and cell species is still controversial. Here, we tried to characterize primary FVIII-producing organ and cell species using genetically engineered mice, in which enhanced green fluorescent protein (EGFP) was expressed instead of the F8 gene. EGFP-positive FVIII-producing cells existed only in thin sinusoidal layer of the liver and characterized as CD31high, CD146high, and lymphatic vascular endothelial hyaluronan receptor 1 (Lyve1)+. EGFP-positive cells can be clearly distinguished from lymphatic endothelial cells in the expression profile of the podoplanin− and C-type lectin-like receptor-2 (CLEC-2)+. In embryogenesis, EGFP-positive cells began to emerge at E14.5 and subsequently increased according to liver maturation. Furthermore, plasma FVIII could be abolished by crossing F8 conditional deficient mice with Lyve1-Cre mice. In conclusion, in mice, FVIII is only produced from endothelial cells exhibiting CD31high, CD146high, Lyve1+, CLEC-2+, and podoplanin− in liver sinusoidal endothelial cells.

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Psychiatric disorders and impairments in GABAergic neurotransmission: approaches using genetically engineered mice

Neuroscience Research ◽

10.1016/j.neures.2009.09.1514 ◽

2009 ◽

Vol 65 ◽

pp. S8

Author(s):

Yuchio Yanagawa

Keyword(s):

Psychiatric Disorders ◽

Genetically Engineered ◽

Gabaergic Neurotransmission ◽

Genetically Engineered Mice

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Immune Competency of a Hairless Mouse Strain for Improved Preclinical Studies in Genetically Engineered Mice

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-10-0207 ◽

2010 ◽

Vol 9 (8) ◽

pp. 2354-2364 ◽

Cited By ~ 23

Author(s):

Beverly S. Schaffer ◽

Marcia H. Grayson ◽

Joy M. Wortham ◽

Courtney B. Kubicek ◽

Amanda T. McCleish ◽

...

Keyword(s):

Mouse Strain ◽

Hairless Mouse ◽

Genetically Engineered ◽

Preclinical Studies ◽

Genetically Engineered Mice ◽

Immune Competency

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miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice

Journal of Experimental Medicine ◽

10.1084/jem.20101823 ◽

2011 ◽

Vol 208 (6) ◽

pp. 1189-1201 ◽

Cited By ~ 528

Author(s):

Mark P. Boldin ◽

Konstantin D. Taganov ◽

Dinesh S. Rao ◽

Lili Yang ◽

Jimmy L. Zhao ◽

...

Keyword(s):

Molecular Mechanisms ◽

Immune Cell ◽

Myeloid Cell ◽

Genetically Engineered ◽

Biological Processes ◽

Targeted Deletion ◽

Genetically Engineered Mice ◽

Immune Defects ◽

Molecular Brake

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.

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