Gap junctions and the propagation of cell survival and cell death signals

Krysko, Dmitri V.; Leybaert, Luc; Vandenabeele, Peter; D’Herde, Katharina

doi:10.1007/s10495-005-1875-2

Cited by 156 publications

(122 citation statements)

References 126 publications

(158 reference statements)

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“…Indeed, plasma membrane collapse during primary or secondary necrosis is associated with the release of RNA molecules, which interact with TLR3 on DCs, 101 with the release of double-stranded DNA, 102 which stimulates both macrophages and DCs, as well as that of nucleotides, leading to the maturation of DCs 103 along with the activation of the NF-kB pathway. 104 End-stage degradation products from dying tumor cells are able to modulate their recognition by the immune system through a family of innate immunity receptors, the pentraxins.…”

Section: End-stage Degradation Products With Proinflammatory Propertiesmentioning

confidence: 99%

Molecular characteristics of immunogenic cancer cell death

et al. 2007

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Apoptotic cell death is initiated by a morphologically homogenous entity that was considered to be non-immunogenic and noninflammatory in nature. However, recent advances suggest that apoptosis, under certain circumstances, can be immunogenic. In particular, some characteristics of the plasma membrane, acquired at preapoptotic stage, can cause immune effectors to recognize and attack preapoptotic tumor cells. The signals that mediate the immunogenicity of tumor cells involve elements of the DNA damage response (such as ataxia telangiectasia mutated and p53 activation), elements of the endoplasmic reticulum stress response (such as eukaryotic initiation factor 2a phosphorylation), as well as elements of the apoptotic response (such as caspase activation). Depending on the signal-transduction pathway, tumor cells responding to chemotherapy or radiotherapy can express 'danger' and 'eat me' signals on the cell surface (such as NKG2D ligands, heat-shock proteins and calreticulin) or can secrete/release immunostimulatory factors (such as cytokines and high-mobility group box 1) to stimulate innate immune effectors. Likewise, the precise sequence of such events influences the 'decision' of the immune system to mount a cognate response or not. We therefore anticipate that the comprehension of the mechanisms governing the immunogenicity of cell death will have a profound impact on the design of anticancer therapies.

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Section: End-stage Degradation Products With Proinflammatory Propertiesmentioning

confidence: 99%

Molecular characteristics of immunogenic cancer cell death

et al. 2007

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“…In pathological conditions, astrocytes become activated, via the upregulation of glial fibrillary acid protein (GFAP), and have been demonstrated to be capable of protecting neurons from various injuries, including trauma and ischemic insult (18)(19)(20)(21). GJC, the molecular channel allowing the transmission of critical survival-associated secondary messengers, has been shown to be one of the mechanisms underlying this process (22,23). Previous studies have suggested that there are activated astrocytes surrounding glioma cells, and that functional GJC exists between astrocytes and glioma cells (24,25).…”

Section: Introductionmentioning

confidence: 99%

Astrocytes protect glioma cells from chemotherapy and upregulate survival genes via gap junctional communication

Zhao

et al. 2015

Molecular Medicine Reports

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Abstract. Gliomas are the most common type of primary brain tumor. Using current standard treatment regimens, the prognosis of patients with gliomas remains poor, which is predominantly due to the resistance of glioma cells to chemotherapy. The organ microenvironment has been implicated in the pathogenesis and survival of tumor cells. Thus, the aim of the present study was to test the hypothesis that astrocytes (the housekeeping cells of the brain microenvironment) may protect glioma cells from chemotherapy and to investigate the underlying mechanism. Immunofluorescent and scanning electron microscopy demonstrated that glioma cells were surrounded and infiltrated by activated astrocytes. In vitro co-culture of glioma cells with astrocytes significantly reduced the cytotoxic effects on glioma cells caused by various chemotherapeutic agents, as demonstrated by fluorescein isothiocyanate-propidium iodide flow cytometry. Transwell experiments indicated that this protective effect was dependent on physical contact and the gap junctional communication (GJC) between astrocytes and glioma cells. Microarray expression profiling further revealed that astrocytes upregulated the expression levels of various critical survival genes in the glioma cells via GJC. The results of the present study indicated that the organ microenvironment may affect the biological behavior of tumor cells and suggest a novel mechanism of resistance in glioma cells, which may be of therapeutic relevance clinically.

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“…Inhibition of gap junctions prevents cell death (Farahani et al, 2005;de Pina-Benabou et al, 2005;Krysko et al, 2005). We, for the first time, show that PKCγ C1B mutations have a negative effect on endogenous wild type PKCγ.…”

Section: Discussionmentioning

confidence: 65%

“…Loss of control of gap junctions by PKCγ, ie., no PKCγ phosphorylation of Cx50 in PKCγ knockout lenses, causes PKCγ knockout lenses to be more susceptible to oxidative stress-induced cataracts in the mouse (Lin et al, 2006). Inhibition of gap junctions prevents cell death (Farahani et al, 2005;de Pina-Benabou et al, 2005;Krysko et al, 2005). It is apparent that control of gap junctions is essential for lens cell survival.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C γ mutations in the C1B domain cause caspase-3-linked apoptosis in lens epithelial cells through gap junctions

Lin

Shanks

Prakash

et al. 2007

Experimental Eye Research

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Failure to control oxidative stress is closely related to aging and to a diverse range of human diseases. We have reported that protein kinase C γ (PKCγ) acts as a primary oxidative stress sensor in the lens. PKCγ has a Zn-finger C1B stress switch domain, residues 101-150. Mutation, H101Y, in the C1B domain of PKCγ proteins causes a failure of the PKCγ oxidative stress response (Lin and Takemoto (2005) (100 μM, 3 h) activated a caspase-3 apoptotic pathway in the lens epithelial cells but was more severe in cells expressing PKCγ mutations. The presence of 18α-glycyrrhetinic acid (AGA), an inhibitor of gap junctions, decreased Cx43 and Cx50 protein levels and gap junction plaque number. This reduction in gap junctions by AGA resulted in inhibition of H 2 O 2 -induced apoptosis. Our results demonstrate that there is a dominant negative effect of PKCγ C1B mutations on endogenous PKCγ which results in loss of control of gap junctions. Modeled structures suggest that the severity of C1B mutation effects may be related to extent of loss of C1B structure. Mutations in the C1B domain of PKCγ result in increased apoptosis in lens epithelial cells. This can be prevented by a gap junction inhibitor. Thus, propagation of apoptosis from cellto-cell in lens epithelial cells may be through open gap junctions. The control of gap junctions requires PKCγ.

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Gap junctions and the propagation of cell survival and cell death signals

Cited by 156 publications

References 126 publications

Molecular characteristics of immunogenic cancer cell death

Molecular characteristics of immunogenic cancer cell death

Astrocytes protect glioma cells from chemotherapy and upregulate survival genes via gap junctional communication

Protein kinase C γ mutations in the C1B domain cause caspase-3-linked apoptosis in lens epithelial cells through gap junctions

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