Potassium is a critical regulator of apoptotic enzymes in vitro and in vivo

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Introduction

Apoptosis is a necessary biological process by which cells are deleted from a population without damaging nearby cells or eliciting an unwanted inflammatory reaction. The available data suggest that this process is ubiquitous, with all cells capable of undergoing apoptosis in response to the correct stimuli. The highly conserved nature of apoptosis indicates that it must play a critical role in normal biology and implies that defects in this process are likely to have dire consequences. Indeed, a dysfunctional apoptotic program has been implicated in several diseases including cancer, AIDS, and Alzheimer's[1].

Consistent with the conserved occurrence of apoptosis, all dying cells display a remarkably common set of morphological changes[2]. Early during cell death there is a distinct loss of cell volume (cell shrinkage). Adherent cells begin to dissociate from neighboring cells and become rounded. The chromatin in an apoptotic cell coalesces around the periphery of the nucleus and the nucleus then blebs apart within the cytoplasm. Eventually the entire cell disassembles into small, spherical, highly crosslinked structures known as apoptotic bodies which are recognized by neighboring cells or resident macrophages and phagocytosed. Since all cells undergoing apoptosis display these morphological changes, there appears to be a common pathway underlying the death program. Despite conservation of the apoptotic process, not all cells respond to the same apoptotic signals, suggesting there are signal-specific pathways in different cell types that feed into the common death machinery.

Delineating the enzymatic components of the common apoptotic pathway is an area of intense study that has seen considerable advance in recent years. One of the most studied of the cell death enzyme systems is the activation of a nuclease(s) that degrades the genome into discrete oligonucleosomal fragments based on cleavage of the chromatin substructure in the internucleosomal DNA regions3, 4. In addition, chromatin is also cleaved into larger ≈30–50 Kb fragments, presumably via cleavage of a higher order chromatin structure known as a “loop”5, 6, 7, 8, 9, 10. Upstream of DNA degradation, an elaborate enzymatic cascade of proteases is involved in signalling downstream events (such as DNA degradation) as well as degrading bulk macromolecules. These proteases are primarily members of the caspase family of cysteine proteases that are all presumably constitutively expressed as proenzymes and proteolytically activated during apoptosis. These caspases have been shown to function in both the signal-specific as well as the common portions of the death pathway.

While many different signal-specific pathways have their own series of checks and balances (for example phosphatases act as a counterbalance to the activity of kinases), there are very few identified systems that control the “common” portion of the apoptotic pathway. The best known component of these common control systems is the Bcl-2 family of proteins11, 12, 13. Expression of Bcl-2 in many different cell types will suppress apoptosis in response to a myriad of signals, suggesting that Bcl-2 inhibits a common segment of the apoptotic pathway. Recently, evidence from our lab has implicated the intracellular ionic environment, dictated primarily by K+ concentrations, in the global control of the common apoptotic program[14]. In this manuscript we will discuss this new information and the role of K+ as a new ubiquitous inhibitor of the apoptotic pathway.

Section snippets

Ionic control of apoptotic nuclease activity

Apoptosis is primarily a catabolic phenomenon and several systems exist to insure that large macromolecules are degraded rapidly and effectively. The first such system discovered is the destruction of the genome through cleavage in the internucleosomal or linker DNA regions3, 4. This cleavage releases oligonucleosomal DNA fragments that form a very characteristic pattern known as the apoptotic “ladder” on an agarose gel. Chromatin is packaged into a higher order configuration known as a “loop”

Conclusion

The apoptotic program is complex and involves many different signal- and cell-specific pathways that feed into a single common pathway. The checks and balances imposed on the signal-specific portions of these pathways are numerous; however, very few checkpoints have been identified that regulate the common portion of the death pathway. As discussed above, considerable data now support a role for the intracellular ionic environment in providing such a checkpoint. As long as the intracellular

Summary

Apoptosis, or programmed cell death, is a fundamental biological process involved in many physiological and pathological phenomena. This process is predominantly catabolic in which cellular macromolecules are broken down by distinct enzymes to be later recycled in healthy cells. These enzymes are arranged in an elaborate cascade that serves to both propagate and amplify a death signal as well as process bulk macromolecules and inhibit repair systems.

One of the best-characterized enzyme systems

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References (39)

  • L Wang et al.

    Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death

    Cell

    (1994)
  • F.M Hughes et al.

    Glucocorticoid-induced thymocyte apoptosis: protease-dependent activation of cell shrinkage and DNA degradation

    J. Steroid Biochem. Molec. Biol.

    (1998)
  • G Häcker et al.

    The medical significance of physiological cell death

    Med. Res. Rev.

    (1995)
  • J.F.R Kerr et al.

    Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics

    Brit. J. Cancer

    (1972)
  • A.H Wyllie

    Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation

    Nature

    (1980)
  • L.B Kokileva

    DNA degradation in isolated rat liver nuclei

    Mol. Biol. Rep.

    (1979)
  • F Oberhammer et al.

    Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation

    EMBO J.

    (1993)
  • G.M Cohen et al.

    Formation of large molecular weight fragments of DNA is a key committed step of apoptosis in thymocytes

    J. Immunol.

    (1994)
  • P.R Walker et al.

    Detection of the initial stages of DNA fragmentation in apoptosis

    BioTechniques

    (1993)
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      The composition offering best performance was 30% PVC: 61% dioctyl sebacate (DOS): 6% NaTPB and 3% ionophore. K+ is known to be the activator of numerous enzymatic processes, an example being the release of energy during carbohydrate metabolism; hence, even small changes in K+ concentration may result in severe ailments such as arrhythmia among other cardiovascular complications [105–107]. The importance of accurate, cheap and rapid K+ concentration determination methodologies is therefore clear.

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    Present address: Department of Biology, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC 28223, USA.

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