Novel complex of HAT protein TIP60 and nuclear receptor PXR promotes cell migration and adhesion

Karishma, Bakshi; Ranjitha, B.; Dubey, Shraddha; Jagannadham, Jaisri; Jaiswal, Bharti; Gupta, Ashish

doi:10.1038/s41598-017-03783-w

Cited by 21 publications

(15 citation statements)

References 43 publications

(49 reference statements)

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“…It is unclear exactly how the endogenous AFT complex manifests. Several publications report the use of fluorescently tagged AFT complex components [48][49][50][51], but Tip60 in these studies shows a markedly different distribution to those reports using smaller tags, or untagged Tip60 [52][53][54]. Further differences may arise from the use of non-neuronal [51,52] or neuronal-like [53] cell lines.…”

Section: App and Tdp-43 Have Distinct Intracellular Locations In Cultmentioning

confidence: 95%

The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

et al. 2020

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Alzheimer’s disease (AD) is a neurodegenerative condition, of which one of the cardinal pathological hallmarks is the extracellular accumulation of amyloid β (Aβ) peptides. These peptides are generated via proteolysis of the amyloid precursor protein (APP), in a manner dependent on the β-secretase, BACE1 and the multicomponent γ-secretase complex. Recent data also suggest a contributory role in AD of transactive response DNA binding protein 43 (TDP-43). There is little insight into a possible mechanism linking TDP-43 and APP processing. To this end, we used cultured human neuronal cells to investigate the ability of TDP-43 to interact with APP and modulate its proteolytic processing. Immunocytochemistry showed TDP-43 to be spatially segregated from both the extranuclear APP holoprotein and its nuclear C-terminal fragment. The latter (APP intracellular domain) was shown to predominantly localise to nucleoli, from which TDP-43 was excluded. Furthermore, neither overexpression of each of the APP isoforms nor siRNA-mediated knockdown of APP had any effect on TDP-43 expression. Doxycycline-stimulated overexpression of TDP-43 was explored in an inducible cell line. Overexpression of TDP-43 had no effect on expression of the APP holoprotein, nor any of the key proteins involved in its proteolysis. Furthermore, increased TDP-43 expression had no effect on BACE1 enzymatic activity or immunoreactivity of Aβ1-40, Aβ1-42 or the Aβ1-40:Aβ1-42 ratio. Also, siRNA-mediated knockdown of TDP-43 had no effect on BACE1 immunoreactivity. Taken together, these data indicate that TDP-43 function and/or dysfunction in AD is likely independent from dysregulation of APP expression and proteolytic processing and Aβ generation.

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Section: App and Tdp-43 Have Distinct Intracellular Locations In Cultmentioning

confidence: 95%

The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

et al. 2020

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“…In a previous study using PXR-overexpressing human hepatocellular carcinoma HepG2 cells, it was proposed that PXR activation induces morphological change and migration of the cells 33 . Another study using HepG2 cells also indicated that PXR promotes the migration of these cells 37 . Noteworthy, wound healing effect of indirubin was observed at 100 nM but not at higher (10,000 nM) concentration.…”

Section: Discussionmentioning

confidence: 96%

Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing

Tanaka

Uchi

Ito

et al. 2019

Sci Rep

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Indirubin is a potent anti-inflammatory phytochemical derived from indigo naturalis. It is also endogenously produced in the intestine and detected in the circulation in mammals. Indirubin exerts its biological functions via two xenobiotic receptor systems: aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR); however, its effects on wound healing remain elusive. To investigate whether indirubin promotes wound healing, we utilized an in vitro scratch injury assay and in vivo full-thickness mouse skin ulcer model and assessed wound closure. Indirubin significantly accelerated wound closure in both the scratch assay and the skin ulcer model. Using inhibitors of cell proliferation or migration, indirubin was found to upregulate the migratory but not the proliferative capacity of keratinocytes. Activation of AHR/PXR by indirubin was confirmed by their nuclear translocation and subsequent upregulation of CYP1A1 (AHR), or UGT1A1 mRNA (PXR) and also by luciferase reporter assay (PXR). Although both AHR and PXR were activated by indirubin, its pro-migratory capacity was canceled by PXR inhibition but not by AHR inhibition and was dependent on the JNK pathway. Moreover, activated PXR was detected in the nuclei of re-epithelialized keratinocytes in human skin ulcers. In conclusion, this study shows that the indirubin-PXR-JNK pathway promotes skin wound healing.

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“…In another study, Bakshi et al revealed that PXR is also acetylated on Lys-170 by KAT5, a well-known KAT protein (also called TIP60), that is involved in regulating chromatin remodeling, transcription, and other nuclear processes by acetylating histone and nonhistone proteins. In this study, it was revealed that KAT5 utilizes its NR-box to interact with the LBD region of PXR and acetylates PXR at Lys-170 to induce its intra-nuclear reorganization [88]. Interestingly, these authors observed that PXR interaction with TIP60 augments the catalytic activity of TIP60 towards the acetylation of histone proteins.…”

Section: Acetylationmentioning

confidence: 88%

The Interface between Cell Signaling Pathways and Pregnane X Receptor

Rogers

Parker

Vainer

et al. 2021

Cells

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Highly expressed in the enterohepatic system, pregnane X receptor (PXR, NR1I2) is a well-characterized nuclear receptor (NR) that regulates the expression of genes in the liver and intestines that encode key drug metabolizing enzymes and drug transporter proteins in mammals. The net effect of PXR activation is to increase metabolism and clear drugs and xenobiotics from the body, producing a protective effect and mediating clinically significant drug interaction in patients on combination therapy. The complete understanding of PXR biology is thus important for the development of safe and effective therapeutic strategies. Furthermore, PXR activation is now known to specifically transrepress the inflammatory- and nutrient-signaling pathways of gene expression, thereby providing a mechanism for linking these signaling pathways together with enzymatic drug biotransformation pathways in the liver and intestines. Recent research efforts highlight numerous post-translational modifications (PTMs) which significantly influence the biological function of PXR. However, this thrust of research is still in its infancy. In the context of gene-environment interactions, we present a review of the recent literature that implicates PXR PTMs in regulating its clinically relevant biology. We also provide a discussion of how these PTMs likely interface with each other to respond to extracellular cues to appropriately modify PXR activity.

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Novel complex of HAT protein TIP60 and nuclear receptor PXR promotes cell migration and adhesion

Cited by 21 publications

References 43 publications

The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing

The Interface between Cell Signaling Pathways and Pregnane X Receptor

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