Reciprocal regulation of p53 and NF-κB by diacylglycerol kinase ζ

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Abstract

Diacylglycerol kinase (DGK) participates in lipid mediated-signal transduction. It phosphorylates diacylglycerol (DG) to phosphatidic acid (PA), thereby regulating the balanced control of these second messenger actions. Previous reports have described that one DGK family, DGKζ, is closely involved in stress responses under various conditions. Cellular stress response, a physiological process enabling cells to cope with an altered environment, is finely tuned through various signaling cascades and their molecular crosstalk. The major components of stress response are p53 and NF-κB. p53 generally serves as a proapoptotic transcriptional factor, whereas NF-κB promotes resistance to programmed cell death under most circumstances.

Recent studies have suggested that DGKζ facilitates p53 degradation in cytoplasm through ubiquitin proteasome system and that DGKζ deletion upregulates p53 protein levels under basal and DNA-damage conditions. Counter-intuitively, however, DGKζ deletion suppresses p53 transcriptional activity despite increased p53 levels. In contrast, DGKζ knockdown engenders enhancement of NF-κB pathway in response to cytokines such as TNF-α and IL-1β. In response to these cytokines, DGKζ downregulation accelerates phosphorylation of the p65 subunit and its nuclear translocation, thereby enhancing NF-κB transcriptional activity. Furthermore, DGKζ deficiency is shown to promote increased association of p65 subunit with the transcriptional cofactor CBP. It is particularly interesting that this association is observed even under basal conditions in the absence of stimulation. These findings suggest that DGKζ plays a role in sequestration of the limiting pool of CBP/p300 between the NF-κB p65 subunit and p53, and that DGKζ downregulation shifts CBP/p300 toward the NF-κB subunit to regulate reciprocally antagonistic phenotypes of these transcription factors.

Introduction

Lipid metabolism plays a crucially important role in our lives. It is closely associated with energy storage and expenditure. It is noteworthy that lipid metabolism is relevant not only to energy homeostasis but also to cellular structure and signal transduction. Triglyceride (TG) is the most efficient storage form of energy. However, phospholipids are the major constituent of membrane structure with amphipathic nature, thereby efficiently forming the boundary of an individual cell and compartmentalizing the subcellular organelles. Phospholipids consist of several species with different acyl chains and head groups. Of these, phosphoinositide (PI) is involved intimately in signal transduction, in which a second messenger diacylglycerol (DG) is produced through enzymatic cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) by phospholipase C (Berridge, 1987). Actually, the DG signal activates various molecules containing DG-responsive elements, thereby triggering widely various physiological processes including neuronal function (Tu-Sekine et al., 2015). Therefore, this signaling system is expected to be tightly controlled; otherwise it would cause pathological reactions such as dysregulation of differentiation, proliferation, and cell death (Nishizuka, 1992). DG kinase (DGK) is an enzyme that is primarily involved in attenuation of DG signal through its phosphorylation into phosphatidic acid (PA) (Baldanzi, 2014, Kanoh et al., 1990).

Results of recent studies suggest that DG signaling machinery is widely present not only in plasma membrane but also in other subcellular compartments such as the endoplasmic reticulum, cytoskeleton, and nucleus. Consistent with this ubiquitously operated machinery within the cell, DGK reportedly consists of several isozymes, which show unique subcellular distribution (Goto et al., 2007, Sakane et al., 2007, Topham and Epand, 2009). These findings suggest that the DG signal is regulated independently by a unique DGK isozyme at a distinct subcellular site. Of these, DGKζ is characterized by a nuclear localization signal (NLS). It localizes primarily to the nucleus (Bunting et al., 1996, Evangelisti et al., 2010, Goto and Kondo, 1996). Therefore, DGKζ is presumably involved in nuclear events such as regulation of transcriptional control. Actually, DGKζ exerts a positive regulation on the tumor suppressor p53, which plays a master role in cell death under various stress conditions (Tanaka et al., 2013). Furthermore, DGKζ is engaged in the regulation of anther transcription factor nuclear factor-κB (NF-κB), which is relevant to cell survival signaling (Tsuchiya et al., 2015). Herein, we review how DGKζ is involved in the regulatory mechanisms of the transcription factors p53 and NF-κB, two major signaling machineries of cell death and survival.

Section snippets

DGKζ deficiency attenuates p53 transcriptional activity

DGKζ was identified as an isozyme that contains an NLS and which localizes to the nucleus (Goto and Kondo, 1996). Reports of immunohistochemical analyses have described its nuclear localization in native cells of various types, including neurons (Goto et al., 2007, Hozumi et al., 2003, Sasaki et al., 2006). In addition to the NLS, functional nuclear export signal (NES) was also identified in DGKζ (Evangelisti et al., 2010), suggesting that this isozyme shuttles between the nucleus and the

DGKζ downregulation enhances NF-κB transactivation activity

The transcription factor NF-κB plays a pivotal role in regulating inflammation, innate and adaptive immune response, cell growth and survival, and oncogenesis (DiDonato et al., 2012, Ukaji and Umezawa, 2014, Verstrepen et al., 2008). NF-κB is typically composed of heterodimer of p50 and RelA/p65 subunits and is tethered to the cytoplasm in an inactive form via the inhibitor of κB (IκB) inhibitory molecules under normal conditions (Fig. 2A). Upon stimulation with cytokines and

DGKζ is implicated in the regulation of cross-talk between p53 and NF-κB

Transcription factors p53 and NF-κB are critical regulators of reciprocal signaling machineries of cell death and survival. Previously, NF-κB was thought to participate in cell death signals because NF-κB was apparently activated under conditions in which neurons die after seizures or ischemic stroke (Grilli and Memo, 1999). However, the interpretation that NF-κB plays an active role in killing neurons was based largely on the phenomenology of the response. Recent evidence shows that NF-κB

Conclusions

DGKζ has long been implicated in transcriptional control in the nucleus. Recent studies disclose its modulatory effects on the major transcription factors p53 and NF-κB. Interestingly, DGKζ downregulation exerts a reciprocal effect on p53 and NF-κB transactivation activities. It is speculated that DGKζ may regulate the balanced control of the association between these transcription factors and coactivator CBP/p300. However, much remains to be determined as to the functional significance of the

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgments

This work was supported by Grands-in-Aid from The Ministry of Education, Culture, Sports, and Technology (MEXT) of Japan (K.G.) and by GlaxoSmithKline (GSK) Japan Research Grant (T.T.).

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