Individual expression features of GPX2, NQO1 and SQSTM1 transcript variants induced by hydrogen peroxide treatment in HeLa cells

Belanova, Anna; Smirnov, D. S.; Makarenko, Maksim; Belousova, Mariya; Машкина, Е. В.; Александрова, А. А.; Soldatov, A. V.; Zolotukhin, Peter

doi:10.1590/1678-4685-gmb-2016-0005

Cited by 3 publications

(3 citation statements)

References 45 publications

(54 reference statements)

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“…Nevertheless, the existing data unambiguously point out that these circuits are an essential feature of the NRF2/AP-1 pathway. These circuits must be accounted in all applicationsstarting from cell sensor-based pharmacological screening techniques [119,120] and ending with therapeutical research and development [121].…”

Section: Resultsmentioning

confidence: 99%

Feed-Forward and Feed-Back Circuits of the NRF2/AP-1 Composite Pathway

Zolotukhin¹,

Belanova²

2016

A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2

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Being the central regulator of oxidative status of the cell, NRF2 must be regulated so that its activity can be rapidly and strongly induced when needed and quickly suppressed when not. Moreover, for the cell, NRF2 means much more than just antioxidant defense. Numerous general functions rely on NRF2 and related factors. All this implies that the NRF2 pathway has peculiar and powerful mechanisms of control of its activity. To a great extent, these mechanisms are based on feed-forward and feedback circuits. These circuits, more than a dozen, are in the focus of this chapter.intriguing since central proteasomal [2], autophagic [3], general signaling [4,5], and, moreover, cell proliferation, cell cycle and survival regulation factors [1] are in fact NRF2 targets.Although 645 of the 1055 Nrf2 target genes were found to have basal type of expression regulation by this factor [1], Nrf2 is still required to be present in the nucleus in significant amounts to drive their expression. Notably, most of these genes are not at all related to antioxidant and xenobiotic defense systems, i.e., they are essential for proliferation and basic functioning of the cell. Thus, basal expression driven by NRF2 is important for the cell, but to what extent? One should bear in mind that NRF2 knockouts are nonlethal and generally appear normal in stable laboratory conditions [6], yet they are susceptible to numerous diseases [7-9], especially when the housing conditions are suboptimal [6,[10][11][12]. This confirms that basal NRF2 functioning, although not vital, is critical for the cell and organism even when no pro-oxidant or xenobiotic exposure is present.It implies that some cellular mechanisms serve to provide the cell with at least minimal necessary NRF2 activity. On the other hand, it is inherently important for an inducible antioxidant and xenobiotic defense pathway to act as quickly as possible, thus signal amplification is required whenever the initial stimulus is applied. These two distinct prerequisites for normal cell functioning in ever-changing environment appear to be resolved in principle similarly: there are feed-forward circuits that maintain steady-state level of the NRF2 activity and make signal amplification possible when fast cellular reactions are required.Conversely, too much NRF2 activity is no better than its absence: Keap1-null mice demonstrate postnatal lethality [13,14], an effect coinciding with nuclear Nrf2 localization [14] and reversed by Nrf2 downregulation [13]. In this case, several feed-back circuits protect the cell and organism from obsessive NRF2 activation.Most of the feed-forward and feed-back circuits of the NRF2 pathway also involve the closely related transcription factor activator protein 1 (AP-1) represented by homodimers of Jun proteins (JUN, JUNB, JUND) or heterodimers of Fos (FOS, FOSB, FOSL1, FOSL2) and Jun proteins. There are also other dimers of Jun/Fos proteins-e.g. with Atf-proteins [15-17]-still referred to as AP-1 complexes (although either Jun or Fos proteins are absent), and oligom...

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Section: Resultsmentioning

confidence: 99%

Feed-Forward and Feed-Back Circuits of the NRF2/AP-1 Composite Pathway

Zolotukhin¹,

Belanova²

2016

A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2

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“…Fourth, cellular pathways have all capabilities to individually control degradation or long-term storage of mature mRNA variants of a single gene [56][57][58]. Individual transcript expression-based studies are rare due to technical and interpretative difficulties [59,60], but previously we demonstrated that this approach is highly promising in case of oxidative status pathways used for development of systemic biomarkers [28].…”

Section: Analytical Levelsmentioning

confidence: 99%

“…No less importantly, targets of the most complex and clinically relevant pathways are well known. And as it is shown further, these targets that may serve as biomarker panel candidates are not only mRNAs or proteins, but as well individual transcript variants, pre-mRNAs and miRNAs [25][26][27][28]. Consequently, although there are more data to be collected, these pathways may be utilized for developing systemic biomarkers for diagnostics of different health conditions using sets of individual RNAs, proteins and small molecules in analytically convenient combinations.…”

Section: Introductionmentioning

confidence: 99%

Oxidative Status Pathways: Systemic Biomarkers

Zolotukhin¹,

Chmykhalo²,

Belanova³

et al. 2018

Biomarker - Indicator of Abnormal Physiological Process

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Systemic biomarkers (i.e. biomarkers of functioning of cellular pathways) offer a broad spectrum of diagnostic capabilities. There are several approaches to using systemic biomarkers that derive from exact needs of a researcher or a clinical specialist. First, analyzing a multifunctional and multi-systemic pathway in circulating cells (e.g. leukocytes) allows to gather generalized information on functioning of the organism. Second, there are numerous pathways that, even still in circulating cells, allow to assess risks of developing or stage of development of numerous diseases, including the leaders of non-infection diseases mortality-cardiovascular diseases. Third, biopsy specimens can readily be used to assess the exact signaling type of a disease (especially cancer) thus helping in selecting the best treatment option. Due to unique properties of the human oxidative status pathways that are discussed in the present chapter, diagnostics specialists are now acquiring an allin-one toolbox for profiling and detecting almost any non-infectious and a broad range of infectious diseases. In addition to properties of the human oxidative status pathways opening these possibilities, this chapter considers exact systemic biomarkers deriving from this approach, reveals some examples of usage of the resulting diagnostic technology and provides instances of successful clinical application of the systemic biomarker approach.

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