Vertebrate cell death in energy-limited conditions and how to avoid it: what we might learn from mammalian hibernators and other stress-tolerant vertebrates

Presumably to conserve energy, many mammals enter into hibernation during the winter. Homeostatic processes such as transcription and translation are virtually arrested. To further elucidate transcriptional regulation during hibernation, we studied the transcription factor p53. Here, we demonstrate that changes in liver mRNA and protein concentrations of known regulators of p53 are consistent with activation. p53 mRNA and protein concentrations are unrelated. Importantly, p53 protein concentration is increased ~2-fold during the interbout arousal that punctuates bouts of torpor. As a result, both the interbout arousal and the torpid state are characterized by high levels of nuclear-localized p53. Chromatin immunoprecipitation assays indicate that p53 binds DNA during the winter. Furthermore, p53 recruits RNA polymerase II, as indicated by nuclear run-on data. However, and consistent with previous data indicating an arrest of transcriptional elongation during torpor, p53 'activity' does not result in expected changes in target gene transcripts. These data demonstrate the importance of using a systems level-approach in understanding a complex phenotype such as mammalian hibernation. Relying on interpretations of data that are based on steady-state regulation in other systems may be misleading in the context of non-steady-state conditions such as torpor. KEY WORDS: Torpor, Nuclear run-on, Metabolic depression INTRODUCTIONDuring the winter, hibernating mammals such as ground squirrels oscillate between bouts of metabolic depression (torpor), wherein core body temperature may be below −2°C, and euthermic periods (interbout arousals), wherein body temperature approaches euthermic values (~36°C) (van Breukelen and Martin, 2002; Carey et al., 2003). Oxygen consumption during torpor may be as low as 1/100th of the active rate (Carey et al., 2003). Hibernation represents a unique metabolic constraint. Hibernators must balance a need to conserve energy with maintenance of cellular structure. Many energetically expensive physiological processes normally vital to homeostasis are dramatically reduced during torpor. Processes such as transcription and translation are not sustainable given the severe metabolic depression. Earlier, we demonstrated marked depressions of both hepatic transcription and translation (van Breukelen and Martin, 2001;van Breukelen and Martin, 2002). Nuclear run-on data from hibernating golden-mantled ground squirrels demonstrate a moderate inhibition of transcriptional initiation (~50%), but indicate RESEARCH ARTICLESchool of Life Sciences, University of Nevada, Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154, USA. that elongation of transcripts is essentially arrested during torpor (van Breukelen and Martin, 2002). Translational regulation during hibernation is more elaborate. Polysome analyses reveal that the bulk of initiation is depressed as animals enter into torpor (van Breukelen and Martin, 2001). 4E-binding protein 1, a potent regulator of the cap binding protein, eIF4E, is absent...

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“…These processes are important during hibernation, e.g. apoptosis must be regulated during hibernation (van Breukelen et al, 2010).…”

Section: Research Articlementioning

confidence: 99%

“…These processes are important during hibernation, e.g. apoptosis must be regulated during hibernation (van Breukelen et al, 2010).At least 160 proteins have been reported to regulate p53 activity (Toledo and Wahl, 2006). During steady-state conditions, changes in mRNA or protein abundance of p53 regulatory proteins have…”

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confidence: 99%

A systems-level approach to understanding transcriptional regulation by p53 during mammalian hibernation

Pan

Treat

Breukelen

2014

Journal of Experimental Biology

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“…Despite the adaptive value of the dormant phenotype, dormancy in vertebrates may expose cells to diverse stressors, including fluctuations in temperature or oxygen levels, acidosis, and oxidative damage (54). Moreover, because dormancy entails prolonged periods of inactivity and fasting, an expected outcome arising from organ and tissue disuse is cellular atrophy and the potential for compromised performance upon arousal.…”

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confidence: 99%

Frogs and estivation: transcriptional insights into metabolism and cell survival in a natural model of extended muscle disuse

Reilly

Schlipalius

Cramp

et al. 2013

Physiological Genomics

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Reilly BD, Schlipalius DI, Cramp RL, Ebert PR, Franklin CE. Frogs and estivation: transcriptional insights into metabolism and cell survival in a natural model of extended muscle disuse. Physiol Genomics 45: [377][378][379][380][381][382][383][384][385][386][387][388] 2013. First published April 2, 2013; doi:10.1152/physiolgenomics.00163.2012.-Green-striped burrowing frogs (Cyclorana alboguttata) survive in arid environments by burrowing underground and entering into a deep, prolonged metabolic depression known as estivation. Throughout estivation, C. alboguttata is immobilized within a cast-like cocoon of shed skin and ceases feeding and moving. Remarkably, these frogs exhibit very little muscle atrophy despite extended disuse and fasting. Little is known about the transcriptional regulation of estivation or associated mechanisms that may minimize degradative pathways of atrophy. To investigate transcriptional pathways associated with metabolic depression and maintenance of muscle function in estivating burrowing frogs, we assembled a skeletal muscle transcriptome using nextgeneration short read sequencing and compared gene expression patterns between active and 4 mo estivating C. alboguttata. This identified a complex suite of gene expression changes that occur in muscle during estivation and provides evidence that estivation in burrowing frogs involves transcriptional regulation of genes associated with cytoskeletal remodeling, avoidance of oxidative stress, energy metabolism, the cell stress response, and apoptotic signaling. In particular, the expression levels of genes encoding cell cycle and prosurvival proteins, such as serine/threonine-protein kinase Chk1, cell division protein kinase 2, survivin, and vesicular overexpressed in cancer prosurvival protein 1, were upregulated during estivation. These data suggest that estivating C. alboguttata are able to regulate the expression of genes in several major cellular pathways critical to the survival and viability of cells, thus preserving muscle function while avoiding the deleterious consequences often seen in laboratory models of muscle disuse. aestivation; dormancy; apoptosis; survivin; RNA-Seq UNDER ADVERSE ENVIRONMENTAL conditions many organisms enter dormancy, a period of inactivity that prolongs the amount of time an animal can survive on endogenous fuel reserves. Dormancy involves strong suppression of both locomotor activity and metabolic rate and is a common factor of various survival strategies including hibernation, torpor, anhydrobiosis, and diapause (49). Under circumstances of food and water deprivation associated with xeric conditions, numerous animals (invertebrates, fish, frogs, reptiles) become dormant by entering into a metabolically depressed state known as estivation. Whole animal metabolism during estivation may be depressed by as much as 80% and can sustain viability for an entire dry season, if not years (23,53).Despite the adaptive value of the dormant phenotype, dormancy in vertebrates may expose cells to diverse stressors, includi...

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“…It is tempting to speculate that S-glutathionylation of caspase-3 in HUVECs (57) may constitute a regulatory mechanism to control aberrant activation of caspase-3 due to various oxidative and metabolic stresses (11,79) in the umbilical vein (74,83). In conditions of overt inflammation, accompanied by release of TNFa, HUVECS induce de-glutathionylation of caspase-3, and subsequently undergo cell death.…”

Section: Redox-based Regulation Of Caspases 8 Andmentioning

confidence: 99%

Redox-Based Regulation of Apoptosis: S-Glutathionylation As a Regulatory Mechanism to Control Cell Death

Anathy

Roberson

Guala

et al. 2012

Antioxidants & Redox Signaling

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Significance: Redox-based signaling governs a number of important pathways in tissue homeostasis. Consequently, deregulation of redox-controlled processes has been linked to a number of human diseases. Among the biological processes regulated by redox signaling, apoptosis or programmed cell death is a highly conserved process important for tissue homeostasis. Apoptosis can be triggered by a wide variety of stimuli, including death receptor ligands, environmental agents, and cytotoxic drugs. Apoptosis has also been implicated in the etiology of many human diseases. Recent Advances: Recent discoveries demonstrate that redox-based changes are required for efficient activation of apoptosis. Among these redox changes, alterations in the abundant thiol, glutathione (GSH), and the oxidative post-translational modification, protein S-glutathionylation (PSSG) have come to the forefront as critical regulators of apoptosis. Critical Issues: Although redox-based changes have been documented in apoptosis and disease pathogenesis, the mechanistic details, whereby redox perturbations intersect with pathogenic processes, remain obscure. Future Directions: Further research will be needed to understand the context in which of the members of the death receptor pathways undergo ligand dependent oxidative modifications. Additional investigation into the interplay between oxidative modifications, redox enzymes, and apoptosis pathway members are also critically needed to improve our understanding how redoxbased control is achieved. Such analyses will be important in understanding the diverse chronic diseases. In this review we will discuss the emerging paradigms in our current understanding of redox-based regulation of apoptosis with an emphasis on S-glutathionylation of proteins and the enzymes involved in this important posttranslational modification. Antioxid. Redox Signal. 16,[496][497][498][499][500][501][502][503][504][505]

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Vertebrate cell death in energy-limited conditions and how to avoid it: what we might learn from mammalian hibernators and other stress-tolerant vertebrates

Cited by 34 publications

References 131 publications

A systems-level approach to understanding transcriptional regulation by p53 during mammalian hibernation

A systems-level approach to understanding transcriptional regulation by p53 during mammalian hibernation

Frogs and estivation: transcriptional insights into metabolism and cell survival in a natural model of extended muscle disuse

Redox-Based Regulation of Apoptosis: S-Glutathionylation As a Regulatory Mechanism to Control Cell Death

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