scholarly journals Post-Translational Deimination of Immunological and Metabolic Protein Markers in Plasma and Extracellular Vesicles of Naked Mole-Rat (Heterocephalus glaber)

2019 ◽  
Vol 20 (21) ◽  
pp. 5378 ◽  
Author(s):  
Matthew E. Pamenter ◽  
Pinar Uysal-Onganer ◽  
Kenny W. Huynh ◽  
Igor Kraev ◽  
Sigrun Lange
Keyword(s):  
Extracellular Vesicles ◽  
Interaction Network ◽  
Lipid Vesicles ◽  
Cancer Resistance ◽  
Protein Markers ◽  
Post Translational Modification ◽  
Functional Protein ◽  
Metabolic Markers ◽  
Mole Rat ◽  
Naked Mole Rat

Naked mole-rats are long-lived animals that show unusual resistance to hypoxia, cancer and ageing. Protein deimination is an irreversible post-translational modification caused by the peptidylarginine deiminase (PAD) family of enzymes, which convert arginine into citrulline in target proteins. Protein deimination can cause structural and functional protein changes, facilitating protein moonlighting, but also leading to neo-epitope generation and effects on gene regulation. Furthermore, PADs have been found to regulate cellular release of extracellular vesicles (EVs), which are lipid-vesicles released from cells as part of cellular communication. EVs carry protein and genetic cargo and are indicative biomarkers that can be isolated from most body fluids. This study was aimed at profiling deiminated proteins in plasma and EVs of naked mole-rat. Key immune and metabolic proteins were identified to be post-translationally deiminated, with 65 proteins specific for plasma, while 42 proteins were identified to be deiminated in EVs only. Using protein-protein interaction network analysis, deiminated plasma proteins were found to belong to KEEG (Kyoto Encyclopedia of Genes and Genomes) pathways of immunity, infection, cholesterol and drug metabolism, while deiminated proteins in EVs were also linked to KEEG pathways of HIF-1 signalling and glycolysis. The mole-rat EV profiles showed a poly-dispersed population of 50–300 nm, similar to observations of human plasma. Furthermore, the EVs were assessed for three key microRNAs involved in cancer, inflammation and hypoxia. The identification of post-translational deimination of critical immunological and metabolic markers contributes to the current understanding of protein moonlighting functions, via post-translational changes, in the longevity and cancer resistance of naked mole-rats.

The use of non-traditional models in the study of cancer resistance—the case of the naked mole rat

Oncogene ◽  
2020 ◽  
Vol 39 (28) ◽  
pp. 5083-5097 ◽  
Author(s):  
Alyssa Shepard ◽  
Joseph L. Kissil
Keyword(s):  
Cancer Resistance ◽  
Mole Rat ◽  
Naked Mole Rat

scholarly journals Molecular evolution of the hyaluronan synthase 2 gene in mammals: implications for adaptations to the subterranean niche and cancer resistance

2015 ◽  
Vol 11 (5) ◽  
pp. 20150185 ◽  
Author(s):  
Christopher G. Faulkes ◽  
Kalina T. J. Davies ◽  
Stephen J. Rossiter ◽  
Nigel C. Bennett
Keyword(s):  
Purifying Selection ◽  
High Molecular Mass ◽  
Hyaluronan Synthase ◽  
Cancer Resistance ◽  
Closely Related Species ◽  
Heterocephalus Glaber ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Subterranean Mammals ◽  
Hyaluronan Synthase 2

The naked mole-rat (NMR) Heterocephalus glaber is a unique and fascinating mammal exhibiting many unusual adaptations to a subterranean lifestyle. The recent discovery of their resistance to cancer and exceptional longevity has opened up new and important avenues of research. Part of this resistance to cancer has been attributed to the fact that NMRs produce a modified form of hyaluronan—a key constituent of the extracellular matrix—that is thought to confer increased elasticity of the skin as an adaptation for living in narrow tunnels. This so-called high molecular mass hyaluronan (HMM-HA) stems from two apparently unique substitutions in the hyaluronan synthase 2 enzyme (HAS2). To test whether other subterranean mammals with similar selection pressures also show molecular adaptation in their HAS2 gene, we sequenced the HAS2 gene for 11 subterranean mammals and closely related species, and combined these with data from 57 other mammals. Comparative screening revealed that one of the two putatively important HAS2 substitutions in the NMR predicted to have a significant effect on hyaluronan synthase function was uniquely shared by all African mole-rats. Interestingly, we also identified multiple other amino acid substitutions in key domains of the HAS2 molecule, although the biological consequences of these for hyaluronan synthesis remain to be determined. Despite these results, we found evidence of strong purifying selection acting on the HAS2 gene across all mammals, and the NMR remains unique in its particular HAS2 sequence. Our results indicate that more work is needed to determine whether the apparent cancer resistance seen in NMR is shared by other members of the African mole-rat clade.

scholarly journals Naked mole rat cells display more efficient DNA excision repair and higher resistance to toxic impacts than mouse cells

2020 ◽  
Vol 22 ◽  
pp. 01017
Author(s):  
Alexey Evdokimov ◽  
Irina Petruseva ◽  
Aleksei Popov ◽  
Olga Koval ◽  
Olga Lavrik
Keyword(s):  
Cell Death ◽  
Mus Musculus ◽  
Excision Repair ◽  
Genotoxic Stress ◽  
Cancer Resistance ◽  
Dna Excision Repair ◽  
Cell Defense ◽  
Regulated Cell Death ◽  
Mole Rat ◽  
Naked Mole Rat

Naked mole rat is the long-lived and tumor-resistant rodent. Naked mole rat possesses multiple adaptations that may contribute to longevity and cancer-resistance. Higher activity of DNA excision repair systems and their faster recovery after genotoxic impact as compare with Mus musculus directly demonstrated in our previous investigation contribute to longevity and cancer resistance of naked mole rat. In the present study the DNA-damage-induced apoptosis in naked mole rat fibroblasts was studied using conventional methods. The ability of naked mole rat cells to undergo regulated cell death in response to genotoxic stress is another group of cell defense mechanisms. Naked mole rat skin fibroblasts were demonstrated to be much more resistant towards proapoptotic reagents methyl methanesulfonate, 5-fluorouracil and etoposide as compared with fibroblasts of Mus musculus. Naked mole rat cells have demonstrated limited apoptotic response and seem to undergo also other-type regulated cell death under severe genotoxic stress.

scholarly journals Dampened PI3K/AKT signaling contributes to cancer resistance of the naked mole rat

2020 ◽  
Author(s):  
Jing Zhao ◽  
Xiao Tian ◽  
Yabing Zhu ◽  
Zhihui Zhang ◽  
Elena Rydkina ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Mammalian Species ◽  
Pi3k Pathway ◽  
Human Cells ◽  
Cancer Resistance ◽  
Tumor Resistance ◽  
Resistant Species ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Transcriptional Changes

AbstractMammalian species have a dramatically different susceptibility to cancer. However, how cancer-resistant species resist oncogenic transformation is not fully understood. Here, we performed a comprehensive analysis of oncogene-induced transcriptional changes in the fibroblasts of a cancer-prone species, the mouse, and three cancer-resistant species, the human, the blind mole rat, and the naked mole rat. We report that multiple cellular processes are more refractory to oncogene-induced transcriptional changes in blind mole-rat, naked mole-rat, or human cells compared to mouse cells, such as cell division, cell adhesion, extracellular matrix organization, and metabolism. Strikingly, naked mole rat cells are more resistant to Ras-induced transcriptional changes compared to the other three species. As a mechanism, we found that critical genes in the PI3K pathway including Akt1 and Pik3ca are downregulated in naked mole rat cells. Activating the PI3K/AKT pathway in the naked mole rat cells renders them susceptible to tumorigenic transformation. This study provides multiple new insights into anti-cancer mechanisms in cancer-resistant species of mammals.Significance statementAnimal species differ greatly in their cancer susceptibility. Cancer rates in the mouse range from 50-90%, while two other rodent species, the naked mole rat and the blind mole rat have only a few cancer cases ever reported. Here we examined the mechanisms responsible these differences by comparing changes in transcription patters in response to oncoproteins in the mouse, naked mole rat, blind mole rat and human cells. The most striking finding was that the naked mole rat cells were resistant to transcriptional changes induced by oncogenic Ras. We found that pathways downstream of Ras were naturally attenuated in the naked mole rat. This finding identifies a novel mechanism that evolved to provide tumor resistance to the naked mole rat.

scholarly journals MicroRNA-mediated inhibition of AMPK coordinates tissue-specific downregulation of skeletal muscle metabolism in hypoxic naked mole-rats

2021 ◽  
Vol 224 (15) ◽  
Author(s):  
Hanane Hadj-Moussa ◽  
Sarah Chiasson ◽  
Hang Cheng ◽  
Liam Eaton ◽  
Kenneth B. Storey ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Rate ◽  
Glycogen Synthase ◽  
Muscle Metabolism ◽  
Severe Hypoxia ◽  
Post Translational Modification ◽  
Rat Skeletal Muscle ◽  
Tissue Specific ◽  
Mole Rat ◽  
Naked Mole Rat

ABSTRACT Naked mole-rats reduce their metabolic requirements to tolerate severe hypoxia. However, the regulatory mechanisms that underpin this metabolic suppression have yet to be elucidated. 5′-AMP-activated protein kinase (AMPK) is the cellular ‘master’ energy effector and we hypothesized that alterations in the AMPK pathway contribute to metabolic reorganization in hypoxic naked mole-rat skeletal muscle. To test this hypothesis, we exposed naked mole-rats to 4 h of normoxia (21% O2) or severe hypoxia (3% O2), while indirectly measuring whole-animal metabolic rate and fuel preference. We then isolated skeletal muscle and assessed protein expression and post-translational modification of AMPK, and downstream changes in key glucose and fatty acid metabolic proteins mediated by AMPK, including acetyl-CoA carboxylase (ACC1), glycogen synthase (GS) and glucose transporters (GLUTs) 1 and 4. We found that in hypoxic naked mole-rats (1) metabolic rate decreased ∼80% and fuel use switched to carbohydrates, and that (2) levels of activated phosphorylated AMPK and GS, and GLUT4 expression were downregulated in skeletal muscle, while ACC1 was unchanged. To explore the regulatory mechanism underlying this hypometabolic state, we used RT-qPCR to examine 55 AMPK-associated microRNAs (miRNAs), which are short non-coding RNA post-transcriptional silencers. We identified changes in 10 miRNAs (three upregulated and seven downregulated) implicated in AMPK downregulation. Our results suggest that miRNAs and post-translational mechanisms coordinately reduce AMPK activity and downregulate metabolism in naked mole-rat skeletal muscle during severe hypoxia. This novel mechanism may support tissue-specific prioritization of energy for more essential organs in hypoxia.

scholarly journals Imiquimod does not elicit inflammatory responses in the skin of the naked mole rat (Heterocephalus glaber)

2020 ◽  
Author(s):  
Mosiany Letura Kisipan ◽  
Rodi Omondi Ojoo ◽  
Titus I. Kanui ◽  
Klas S.P. Abelson
Keyword(s):  
Granular Layer ◽  
Inflammatory Responses ◽  
Cancer Resistance ◽  
Skin Reactions ◽  
Heterocephalus Glaber ◽  
Skin Changes ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Inflammatory Skin ◽  
Skin Conditions

Abstract Objective: Naked mole rat (Heterocephalus glaber) has recently attracted interest in biomedical research due to its exceptional longevity, cancer resistance and tolerance to potentially harmful conditions or stimuli. Given its unique attributes, this study was designed to characterize inflammatory skin reactions of this animal to topical application of imiquimod, a toll-like receptor 7 and 8 agonist that triggers psoriasis-like skin reaction. Results: Imiquimod did not cause the expected psoriasis-like skin changes. There was no epidermal thickening and a straight epidermo-dermal boundary was maintained. There was no parakeratosis and the granular layer of epidermis was well formed. In the dermis, there was no leukocyte infiltration. This points to an exceptional nature of inflammatory/immune responses of this animal, but the mechanism could not be explained by our results. Naked mole rat could be a valuable negative model for studying psoriasis and other inflammatory skin conditions but as a prerequisite, there is need for further investigations to establish the mechanisms behind its lack of response to imiquimod.

scholarly journals High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat

Nature ◽  
2013 ◽  
Vol 499 (7458) ◽  
pp. 346-349 ◽  
Author(s):  
Xiao Tian ◽  
Jorge Azpurua ◽  
Christopher Hine ◽  
Amita Vaidya ◽  
Max Myakishev-Rempel ◽  
...  
Keyword(s):  
Molecular Mass ◽  
High Molecular Mass ◽  
Cancer Resistance ◽  
Mole Rat ◽  
Naked Mole Rat

Cytoprotection and cancer resistance in the longest-lived rodent, the naked mole-rat

2013 ◽  
Vol 48 (7) ◽  
pp. 697
Author(s):  
Kaitlyn N. Lewis ◽  
Rochelle Buffenstein
Keyword(s):  
Cancer Resistance ◽  
Mole Rat ◽  
Naked Mole Rat
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