scholarly journals Human ARF Specifically Inhibits Epimorphic Regeneration in the Zebrafish Heart

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 666
Author(s):  
Solomon Lee ◽  
Robert Hesse ◽  
Stanley Tamaki ◽  
Catharine Garland ◽  
Jason H. Pomerantz
Keyword(s):  
Kinase Inhibitor ◽  
Regenerative Process ◽  
Reading Frame ◽  
Mesenchymal Transition ◽  
Epimorphic Regeneration ◽  
Context Sensitive ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Murine Skeletal Muscle ◽  
Zebrafish Heart

The Alternative Reading Frame (ARF) protein is a tumor suppressor encoded by the Cyclin Dependent Kinase Inhibitor 2A gene in mammals but not lower regenerative vertebrates, and has been previously implicated as a context-sensitive suppressor of regeneration in murine skeletal muscle and humanized ARF-expressing zebrafish fins. This study extends our investigation of the role of ARF in the regeneration of other solid tissues, including the zebrafish heart and the mammalian digit. Heart regeneration after cryoinjury was used to mimic massive myocardial infarction. ARF gene expression was upregulated during the cardiac regenerative process and slowed the rate of morphological recovery. ARF specifically impacts cardiomyocytes, neovascularization, and the endothelial-mesenchymal transition, while not affecting epicardial proliferation. This suggests that in the context of regeneration, ARF is specifically expressed in cells undergoing dedifferentiation. To investigate ARF as a suppressor of epimorphic regeneration in mammalian systems, we also tested whether the absence of ARF was permissive for murine digit regeneration, but found that ARF absence alone was insufficient to significantly alter digit restoration. These findings provide additional evidence that ARF suppresses epimorphic regeneration, but suggests that modulation of ARF alone is insufficient to permit regeneration.

p21−/− Mice Exhibit Spontaneous Articular Cartilage Regeneration Post-Injury

Cartilage ◽  
2019 ◽  
pp. 194760351987634 ◽  
Author(s):  
Christina L. Jablonski ◽  
Bryce A. Besler ◽  
Jahaan Ali ◽  
Roman J. Krawetz
Keyword(s):  
Articular Cartilage ◽  
Kinase Inhibitor ◽  
Cartilage Regeneration ◽  
Cartilage Thickness ◽  
Cartilage Defects ◽  
Post Injury ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cartilage Healing ◽  
Articular Cartilage Regeneration

Objective Recent studies have implicated the cyclin dependent kinase inhibitor, p21, in enhanced tissue regeneration observed in MRL/MpJ “super-healer” mice. Specifically, p21 is downregulated in MRL cells and similar ear hole closure to MRL mice has been observed in p21−/− mice. However, the direct implications of p21 deletion in endogenous articular cartilage regeneration remain unknown. In this study, we investigated the role of p21 deletion in the ability of mice to heal full-thickness cartilage defects (FTCDs). Design C57BL/6 and p21−/− ( Cdkn1atm1Tyj) mice were subjected to FTCD and assessment of cartilage healing was performed at 1 hour, 3 days, 1 week, 2 weeks, and 4 weeks post-FTCD using a 14-point histological scoring system. X-ray microscopy was used to quantify cartilage healing parameters (e.g., cartilage thickness, surface area/volume) between C57BL/6 and p21−/− mice. Results Absence of p21 resulted in increased spontaneous articular cartilage regeneration by 3 days post-FTCD. Furthermore, p21−/− mice presented with increased cartilage thickness at 1 and 2 weeks post-FTCD compared with uninjured controls, returning to baseline by 4 weeks post-FTCD. Conclusions We report that p21−/− mice display enhanced articular cartilage regeneration post-FTCD compared with C57BL/6 mice. Furthermore, cartilage thickness was increased in p21−/− mice at 1 week post-FTCD compared with uninjured p21−/− mice and C57BL/6 mice.

The role of ionic currents in establishing developmental pattern

1981 ◽  
Vol 295 (1078) ◽  
pp. 553-566 ◽  
Keyword(s):  
Cell Membranes ◽  
Direct Evidence ◽  
Ionic Currents ◽  
Regenerative Process ◽  
Thyroid Cell ◽  
Ion Pumps ◽  
Epimorphic Regeneration ◽  
Charged Macromolecules ◽  
Further Development

This paper reviews a theory of pattern establishment and pattern restoration by endogenous ionic currents. These currents are supposed to be generated by a certain separation of ion leaks and ion pumps in cell membranes. In so far as these currents act back to further this separation, they would be part of a regenerative process that initially establishes positional values. Later in development, particularly in epimorphic regeneration, when positional values are restored or extended, these currents are supposed to leak through sites of discontinuity in such values and thus trigger growth. This paper also reviews the factual evidence for this view: evidence that developmental currents are, indeed, very widespread; evidence in a few cases, particularly in Cecropia follicles and in wounded cavy skin, that they can generate substantial voltage differences or gradients; evidence that comparable artificial fields can move charged macromolecules along cell membranes and polarize cell growth; and direct evidence in a few cases, particularly fucoid eggs, Cecropia follicles and regenerating amphibian limbs, that ion currents do, in fact, act back to direct or further development. The paper also presents a particular theory, based upon ionic currents, of the reversal of thyroid cell polarity by serum.

scholarly journals The Role of the Cyclin Dependent Kinase Inhibitor p21cip1/waf1 in Targeting Cancer: Molecular Mechanisms and Novel Therapeutics

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1475 ◽  
Author(s):  
Al Bitar ◽  
Gali-Muhtasib
Keyword(s):  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Biological Activities ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Multiple Signaling ◽  
Made In

p21cip1/waf1 mediates various biological activities by sensing and responding to multiple stimuli, via p53-dependent and independent pathways. p21 is known to act as a tumor suppressor mainly by inhibiting cell cycle progression and allowing DNA repair. Significant advances have been made in elucidating the potential role of p21 in promoting tumorigenesis. Here, we discuss the involvement of p21 in multiple signaling pathways, its dual role in cancer, and the importance of understanding its paradoxical functions for effectively designing therapeutic strategies that could selectively inhibit its oncogenic activities, override resistance to therapy and yet preserve its tumor suppressive functions.

A potential role of cyclin-dependent kinase inhibitor 1 (p21/WAF1) in the pathogenesis of endometriosis: Directions for future research

2019 ◽  
Vol 133 ◽  
pp. 109414
Author(s):  
Nikolaos Zarkadoulas ◽  
Vasilios Pergialiotis ◽  
Dimitrios Dimitroulis ◽  
Konstantinos Stefanidis ◽  
Christos Verikokos ◽  
...  
Keyword(s):  
Potential Role ◽  
Kinase Inhibitor ◽  
Future Research ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
P21 Waf1

Role of the Cyclin-Dependent Kinase Inhibitor CDKN2A in Familial Melanoma

1998 ◽  
Vol 2 (3) ◽  
pp. 172-179 ◽  
Author(s):  
David Hogg ◽  
Herbert Brill ◽  
Ling Liu ◽  
Jose Monzon ◽  
Anne Summers ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Kinase Inhibitor ◽  
Early Stage ◽  
Surgical Excision ◽  
Cyclin Dependent Kinase ◽  
Dominant Form ◽  
Familial Melanoma ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Autosomal Dominant Form

Background: Approximately 8 to 12% of melanoma appears to be inherited in an autosomal dominant form. Although most early stage melanomas can be treated successfully by simple surgical excision, patients with advanced disease are rarely cured even with aggressive chemotherapy and/or immunotherapy. Objective: There is now compelling evidence that germline mutations of the CDKN2A gene on chromosome 9p21 predispose to melanoma in a subset of melanoma-prone families. In this article the evidence for the role of CDKN2A in the genesis of familial melanoma is reviewed and the implications of genetic testing in families with this disease are discussed. Conclusion: The identification and subsequent surveillance of unaffected individuals who have a genetic predisposition to melanoma may lead to the detection of early (curable) melanomas and to a reduction in mortality.

scholarly journals CDKN2A Gene Expression as a Potential Aging Biomarker in Dogs

2021 ◽  
Vol 8 ◽  
Author(s):  
Sára Sándor ◽  
Kitti Tátrai ◽  
Kálmán Czeibert ◽  
Balázs Egyed ◽  
Enikő Kubinyi
Keyword(s):  
Gene Expression ◽  
Kinase Inhibitor ◽  
Brain Aging ◽  
Model Organisms ◽  
Aging Research ◽  
Temporal Muscle ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Age Related ◽  
The Brain

Describing evolutionary conserved physiological or molecular patterns, which can reliably mark the age of both model organisms and humans or predict the onset of age-related pathologies has become a priority in aging research. The age-related gene-expression changes of the Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) gene have been well-documented in humans and rodents. However, data is lacking from other relevant species, including dogs. Therefore, we quantified the CDKN2A mRNA abundance in dogs of different ages, in four tissue types: the frontal cortex of the brain, temporal muscle, skin, and blood. We found a significant, positive correlation between CDKN2A relative expression values and age in the brain, muscle, and blood; however, no correlation was detected in the skin. The strongest correlation was detected in the brain tissue (CDKN2A/GAPDH: r = 0.757, p < 0.001), similarly to human findings, while the muscle and blood showed weaker, but significant correlation. Our results suggest that CDKN2A might be a potential blood-borne biomarker of aging in dogs, although the validation and optimization will require further, more focused research. Our current results also clearly demonstrate that the role of CDKN2A in aging is conserved in dogs, regarding both tissue specificity and a pivotal role of CDKN2A in brain aging.

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