Signals By Kirk Du Plessis
Hien Mondesir
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The previous studies have indicated common regions activated by response inhibition tasks, including those correlates comprising the fronto-parietal network, specifically the IFG, pre-SMA, and parietal regions. For example, Sebastian et al. (2013b), using hybrid tasks combining Simon, Go/NoGo, and stop signals, demonstrated that areas such as the IFG and the bilateral parietal regions showed activation across all tasks. Nonetheless, unique neural networks for the three subcategories of processes underpinning response inhibition have also been suggested (Rubia et al. 2001; Sebastian et al. 2013b; Chevrier et al. 2007; van Velzen et al. 2014; Sebastian et al. 2013a). For example, the Simon task (interference resolution) was found to stimulate the pre-motor and parietal regions to a greater extent than action cancellation (stop signals), whereas action cancellation was found to elicit stronger activation in the bilateral posterior inferior frontal gyrus/insula and the right striatum than action withholding (Go/NoGo) (Sebastian et al. 2013b). Although the above findings provide important preliminary evidence of the potential common and distinct neural underpinnings of different response inhibition tasks, the majority of studies have either explored only a single response inhibition task in small samples with limited statistical power or were challenging to compare, because they employed various different stimuli (e.g., visual, auditory). We are, therefore, hindered from drawing complete conclusions on the common and distinct neural correlates of the subcategory of processes for response inhibition (Swick et al. 2011; Logan et al. 2015). An understanding of the common and unique neural correlates of the subcategories of cognitive processes associated with response inhibition provides critical insight into early detection, diagnostic accuracy, and treatment targets of clinical disorders afflicted by dysfunctional response inhibition (Aron 2011; Chambers et al. 2009). Meta-analytic pooling of all related studies is a powerful statistical tool that combines data sets from a collection of similar studies to obtain a more accurate and robust estimate of the effect size of a given phenomenon (Fox et al. 2014), and thus may serve as a promising approach to studying the common and distinct neural correlates of the three subcategories of processes associated with response inhibition.
Action withholding encompasses future action selection and inhibition, whereas action cancellation goes beyond this to demand inhibition of an ongoing response. This is induced by presenting Go and NoGo signals at the same time point in their respective trials for withholding or presenting stop signals with a delay after a Go signal for cancellation of an already initiated response. The inhibitory load is likely to be higher in cancellation than withholding (Schachar et al. 2007). Studies have suggested that the time difference in presenting the NoGo and stop signals induces distinct activation patterns (Swick et al. 2011; Rubia et al. 2001), such as a greater extent of activation in the right inferior and superior frontal gyri. This notion is partially supported by the results of our subtraction analysis between action withholding and action cancellation (Table 4). The activation differences observed between these two processes suggest that action withholding and cancellation may interact at different times within the action generation or action inhibition process, thus jointly influencing motor response inhibition (Sebastian et al. 2013a; Dambacher et al. 2014; Cieslik et al. 2015).
The desmosomal cadherin Desmoglein-3 (Dsg3) is a core adhesion component in desmosome junctions that occur with high frequency in the stratified squamous epithelial membrane lining the skin and mucous membrane. Dsg3 is identified as a major target of the circulating autoantibodies in Pemphigus Vulgaris (PV), an autoimmune blistering skin disease, and many signaling pathways have been demonstrated to be activated by PV-IgG targeting Dsg3, highlighting its role as a surface regulator in cell signaling. A recent study has revealed an unprecedented role of Dsg3 in the suppression of p53 and shows dysfunction of this pathway in PV. Furthermore, reciprocal crosstalk between p53 and yes-associated protein (YAP) downstream of Dsg3 has been observed in keratinocytes in which increased YAP expression causes suppression of p53 or vice versa. Both p53 and YAP are the crucial nuclear transcription factors involved in regulating cell fate decision, adaptation and tissue integrity in response to environmental and biological cues and are mutually exclusive in human cancer. In this review, we discuss Dsg3 signaling role in keratinocyte response to stress signals, with the highlight on our recent findings of the Dsg3/p53 pathway in the control of cell proliferation and tissue homeostasis, including the DNA integrity, beyond its function in cell-cell adhesion.
The stabilization of p53 is a common response to cellular stress and is one of the key mechanisms by which the p53 function is regulated. Many tumors that retain wild type p53 show defects in this pathway [49]. The stabilization of p53 also seems to be the case in Dsg3 depleted cells since Dsg3 knockdown resulted in an increase of the half-life of p53 protein turnover by approximately two-fold. We showed that such delayed p53 turnover was accompanied by stabilization of MDM2 that may reflect a negative feedback mechanism to control the p53 expression levels [50]. It is worth noting that the stress response of p53 can be obscured by the nature of its fast turnover as we demonstrated by treating cells with the proteasome inhibitor MG132 that revealed greater differences in the levels of p53 expression between the Dsg3 knockdown and control cells [8]. Consistent with the findings from the loss-of-function study, overexpression of Dsg3 resulted in an inverse effect with marked suppression of p53 at both protein and mRNA levels as well as the p53 transcription activity [8]. Furthermore, this regulatory pathway of Dsg3/p53 was consolidated by experiments with several cellular stress responses, such as UV irradiation, genotoxic drug treatment and cyclic mechanical strain, which provoked further enhancement in the levels of p53 and its downstream targets p21Waf1/Cip1 and Bax in cells with Dsg3 knockdown [8]. Collectively, these results suggest strongly that Dsg3 indeed functions as a sensor by modulating the p53 response to stress signals.
The specificity of p53 induction elicited by PV-IgG targeting Dsg3 was verified by additional in vitro studies with PV sera that contain a pool of anti-Dsg3 antibodies (i.e. polyclonal antibodies) and also with the well-characterized specific pathogenic monoclonal antibody AK23 that binds the Dsg3 adhesion site at the N-terminal [74]. The results from both experimental approaches indicated a marked increase of p53 as well as Bax, concomitant with Dsg3 depletion as expected based on several previous studies with PV sera [14,75]. Thus, the observed findings in PV indicate a specific p53 induction associated with PV-IgG induced Dsg3 disturbance as this effect was demonstrated by the treatment of cells with anti-Dsg3 antibody AK23 in a time and dose-dependent manners [8]. Furthermore, it was proved that enhanced p53 is specific since the RNAi mediated p53 knockdown significantly abated the PV sera induced positive p53 signals. These results suggest strongly that activation of the Dsg3/p53 pathway may contribute, at least in part, to PV pathology, with the evidence of early apoptosis that has been shown by others [65,68,76]. This finding may have important implications in clinical diagnosis and also in the development of a novel therapeutic strategy in treating this life-threatening autoimmune disease in the future.
In an attempt to address the involvement of YAP in the Dsg3/p53 pathway, we performed experiments by knocking down of YAP or treating cells with the YAP inhibitor, and our results indicated both approaches caused increased p53 expression and nuclear accumulation (data not shown) (Figure 1). In contrast, transfection of YAP into the Dsg3 depleted cells partially rescued the phenotype of the p53 induction. Furthermore, the antagonistic regulation between YAP and p53 was demonstrated by p53 Luciferase assay that showed inhibition of p53 transcription activity in cells with YAP transfection, with an inverse effect observed in cells with YAP knockdown, as compared to the respective controls. Hence, it is speculated that YAP may bridge in or have an influence on the Dsg3/p53 pathway in keratinocytes, as shown in a working model that Dsg3 restricts p53 via YAP. This simplified model illustrates a relationship among these three signaling molecules in keratinocyte response to stress signals (Figure 1). Notably, this model places Dsg3 upstream of p53 and YAP and indicates that modulation of Dsg3 could have an impact on both signaling pathways, highlighting Dsg3 as an important component of the cellular stress response network in keratinocytes. Hence, this is another example among many other upstream regulators that elaborates reciprocal crosstalk between YAP and p53 for fine-tuning of cell proliferation and apoptosis [81,82].
In summary, our recent studies provide novel evidence that Dsg3 plays a role in regulating p53 response to stress signals in keratinocytes and this pathway likely involves YAP that acts in the suppression of the p53 pathway. Alterations of this pathway may attribute to the pathogenesis of PV where Dsg3 is targeted by autoantibodies resulting in its degradation (loss of function), leading to heightened p53 levels and the activation of the apoptotic machinery. As a consequence, disruption of cell adhesion and cell shrinkage occurs that causes blistering in the Dsg3 baring tissues. The direct evidence of p53 in PV was lacking, and this study fills this gap, suggesting that Dsg3 signaling towards p53 likely reflects cellular stress response in PV. Hence this finding underscores a central role for Dsg3 in pemphigus pathogenesis. The finding also advances our understanding of normal physiological conditions. For instance, the distinct expression patterns of Dsg3 between the skin and mucous membrane may reflect their exposures to different environmental stresses and insults. While the oral mucous membrane is subject to physical and chemical insults daily, the skin is readily prone to UV irradiation with relative less frequency of mechanical stimulation (e.g. trunk skin). Thus this study sheds a light on a potential role for Dsg3 in control of tissue integrity (including the DNA) and homeostasis in these stress-bearing tissues and indicates the pivotal function of Dsg3 as a stress sensor and responder in keratinocytes beyond cell-cell adhesion.
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