Preference of IRES-mediated initiation of translation during hibernation in golden-mantled ground squirrels, Spermophilus lateralis

Pan, Peipei; Breukelen, Frank van

doi:10.1152/ajpregu.00748.2010

Cited by 21 publications

(25 citation statements)

References 67 publications

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Section: Introductionmentioning

confidence: 84%

“…These data suggested a role for capindependent mechanisms in promoting differential translation (van Breukelen et al, 2004). Transcripts bearing internal ribosome entry sites preferentially accumulate on ribosomes during the torpor bout (Pan and van Breukelen, 2011).Some investigators noted that transcription factors such as p53 and NF-κB move in and out of the nucleus during the torpor cycle (Fleck and Carey, 2005; Allan and Storey, 2012). An earlier study indicated that nuclear p53 protein concentration was significantly reduced by 4-fold in torpid ground squirrels (Fleck and Carey, 2005).…”

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confidence: 99%

“…Melting curve analyses showed no primer-dimers or non-specific products. The efficiency of the primers was controlled as described previously (Pan and van Breukelen, 2011). …”

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confidence: 99%

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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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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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Section: Introductionmentioning

confidence: 84%

mentioning

confidence: 99%

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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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“…Hibernating ground squirrels are an excellent model system for uncovering mechanisms involved in mRNA processing in response to stress since they demonstrate a marked global decrease in transcription (Morin and Storey 2006) and translation (Frerichs et al 1998) during torpor yet show increases in the levels of selected mRNA/protein species (Pan and van Breukelen 2011). While a suite of transcriptional and posttranscriptional controls vital to achieving this molecular restructuring has been described (Hittel and Storey 2002;Storey and Storey 2004;Morin and Storey 2009;Kornfeld et al 2012;Wu and Storey 2012), many regulatory mechanisms remain to be described during hibernation.…”

Section: Discussionmentioning

confidence: 99%

The involvement of mRNA processing factors TIA-1, TIAR, and PABP-1 during mammalian hibernation

Tessier

Audas

et al. 2014

Cell Stress and Chaperones

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Mammalian hibernators survive low body temperatures, ischemia-reperfusion, and restricted nutritional resources via global reductions in energy-expensive cellular processes and selective increases in stress pathways. Consequently, studies that analyze hibernation uncover mechanisms which balance metabolism and support survival by enhancing stress tolerance. We hypothesized processing factors that influence messenger ribonucleic acid (mRNA) maturation and translation may play significant roles in hibernation. We characterized the amino acid sequences of three RNA processing proteins (T cell intracellular antigen 1 (TIA-1), TIA1-related (TIAR), and poly(A)-binding proteins (PABP-1)) from thirteen-lined ground squirrels (Ictidomys tridecemlineatus), which all displayed a high degree of sequence identity with other mammals. Alternate Tia-1 and TiaR gene variants were found in the liver with higher expression of isoform b versus a in both cases. The localization of RNA-binding proteins to subnuclear structures was assessed by immunohistochemistry and confirmed by subcellular fractionation; TIA-1 was identified as a major component of subnuclear structures with up to a sevenfold increase in relative protein levels in the nucleus during hibernation. By contrast, there was no significant difference in the relative protein levels of TIARa/ TIARb in the nucleus, and a decrease was observed for TIAR isoforms in cytoplasmic fractions of torpid animals. Finally, we used solubility tests to analyze the formation of reversible aggregates that are associated with TIA-1/R function during stress; a shift towards the soluble fraction (TIA-1a, TIA-1b) was observed during hibernation suggesting enhanced protein aggregation was not present during torpor. The present study identifies novel posttranscriptional regulatory mechanisms that may play a role in reducing translational rates and/or mRNA processing under unfavorable environmental conditions.

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“…Taken together, mammalian hibernators are subject to substantial transcriptional and posttranscriptional regulation, and various mechanisms have been elucidated to date (Storey and Storey 2004b). For example, work spanning a range of mammalian hibernators has identified epigenetic controls that coordinate the global suppression of transcription (Morin and Storey 2009), the involvement of transcription factors, and their role in achieving a directed cellular response to the various stresses faced as a result of hibernation (Carey et al 2000;Cai et al 2004;Lee et al 2007;Mamady and Storey 2008;Morin et al 2008b;El Kebbaj et al 2009;Tessier and Storey 2012), microRNAs which exert reversible control over translation (Morin et al 2008a;Liu et al 2010;Kornfeld et al 2012), posttranslational modifications which influence the formation of the 48S preinitiation complex (Wu and Storey 2012;Van Breukelen et al 2004), and the disaggregation of polyribosomes during hibernation (Knight et al 2000;Hittel and Storey, 2002;Pan and Van Breukelen 2011).…”

Section: Introductionmentioning

confidence: 99%

To be or not to be: the regulation of mRNA fate as a survival strategy during mammalian hibernation

Tessier

Storey

2014

Cell Stress and Chaperones

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Mammalian hibernators undergo profound behavioral, physiological, and biochemical changes in order to cope with hypothermia, ischemia-reperfusion, and finite fuel reserves over days or weeks of continuous torpor. Against a backdrop of global reductions in energyexpensive processes such as transcription and translation, a subset of genes/proteins are strategically upregulated in order to meet challenges associated with hibernation. Consequently, hibernation involves substantial transcriptional and posttranscriptional regulatory mechanisms and provides a phenomenon with which to understand how a set of common genes/proteins can be differentially regulated in order to enhance stress tolerance beyond that which is possible for nonhibernators. The present review focuses on the involvement of messenger RNA (mRNA) interacting factors that play a role in the regulation of gene/protein expression programs that define the hibernating phenotype. These include proteins involved in mRNA processing (i.e., capping, splicing, and polyadenylation) and the possible role of alternative splicing as a means of enhancing protein diversity. Since the total pool of mRNA remains constant throughout torpor, mechanisms which enhance mRNA stability are discussed in the context of RNA binding proteins and mRNA decay pathways. Furthermore, mechanisms which control the global reduction of cap-dependent translation and the involvement of internal ribosome entry sites in mRNAs encoding stress response proteins are also discussed. Finally, the concept of regulating each of these factors in discrete subcellular compartments for enhanced efficiency is addressed. The analysis draws on recent research from several well-studied mammalian hibernators including ground squirrels, bats, and bears.

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Preference of IRES-mediated initiation of translation during hibernation in golden-mantled ground squirrels, Spermophilus lateralis

Abstract: Pan P, van Breukelen F. Preference of IRES-mediated initiation of translation during hibernation in golden-mantled ground squirrels, Spermophilus lateralis.

Cited by 21 publications

References 67 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

The involvement of mRNA processing factors TIA-1, TIAR, and PABP-1 during mammalian hibernation

To be or not to be: the regulation of mRNA fate as a survival strategy during mammalian hibernation

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