Losing p53 loosens up ER-stress

Byun, Sun‐Sig; Namba, Takushi; Lee, Sam W.

doi:10.18632/aging.100847

Cited by 6 publications

(6 citation statements)

References 7 publications

(12 reference statements)

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“…In this regard, the recovery of p53 in AgRP neurons of AgRPp53 KO mice fed a HFD, reversed their obese phenotype, and stimulated BAT thermogenesis. Moreover, our results are also in agreement with an in vitro study demonstrating that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding, suggesting that defects in the p53 complex represents a new mechanism for ER function modulation 59 , 60 . Furthermore, we found that obese AgRPp53 KO mice centrally treated with TUDCA showed a reduction in food intake, body weight, and adiposity.…”

Section: Discussionsupporting

confidence: 91%

p53 in AgRP neurons is required for protection against diet-induced obesity via JNK1

et al. 2018

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p53 is a well-known tumor suppressor that has emerged as an important player in energy balance. However, its metabolic role in the hypothalamus remains unknown. Herein, we show that mice lacking p53 in agouti-related peptide (AgRP), but not proopiomelanocortin (POMC) or steroidogenic factor-1 (SF1) neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue (BAT) thermogenic activity. AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase (JNK) activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The overexpression of p53 in the ARC or specifically in AgRP neurons of obese mice decreased body weight and stimulated BAT thermogenesis, resulting in body weight loss. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity.

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“…Activation of p53 has been revealed to suppress the activity of the mechanistic target of rapamycin and inhibit the translation of certain proteins (26). The elimination of p53 may provide an opportunity for cancer cells to promote unregulated proliferation due to increased protein synthesis and a subsequent increase in ER function (9). In the current study, the expression of p53 affected the extent of TSA-induced ER stress.…”

Section: Discussionmentioning

confidence: 63%

“…The ER stress response activates cytotoxic mechanisms involving a number of regulatory cytokines associated with the onset of programmed cell death, suggesting this is a possible target in the development of chemotherapeutic agents for inducing cancer cell toxicity (8). As an essential tumor suppressor, the TP53 gene regulates the processes of ER stress, apoptosis, DNA repair, cell cycle and nuclear vesicular trafficking, in the presence of cellular stressors, including hypoxia, DNA damage and oncogene activation (9,10). Previous studies have revealed that p53 is upregulated in response to ER stress and participates in ER stress-induced apoptosis (11).…”

Section: Introductionmentioning

confidence: 99%

Trichostatin A induces p53‑dependent endoplasmic reticulum stress in human colon cancer cells

Dai

Zhang

et al. 2018

Oncol Lett

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Trichostatin A (TSA) has been demonstrated to exhibit various anticancer effects that influence cell cycle arrest, cell proliferation and apoptosis of cancer cells. A potential association between TSA and endoplasmic reticulum (ER) function has been suggested but its anticancer mechanism involving the induction of ER stress is unknown. p53 has previously been demonstrated to regulate ER function in response to stress but its role involving TSA and ER stress in cancer cells is poorly understood. The current study identified that TSA induced ER stress in wild type (WT) HCT116 human colon cancer cells. Following TSA treatment, the ER stress markers GRP78 and GRP94 significantly increased without hyperacetylation of their promoter regions. The inositol-requiring enzyme 1 α (IRE1α)/X-box binding protein 1 (XBP1) pathway was implicated due to an association of phosphorylated IRE1α and spliced XBP1 with ER stress. However, luciferase reporter assay indicated that splicing events were attenuated in HCT116 TP53(-/-) cells. Furthermore, cell viability and apoptosis were revealed to depend on p53 during TSA treatment. Cell viability increased and the apoptosis rate decreased in HCT116 TP53(-/-) cells compared with WT HCT116 cells undergoing TSA treatment. In conclusion, the current study revealed that TSA may induce ER stress via a p53-dependent mechanism in colon cancer cells. This provides information that may assist the development of treatments that exploit the anticancer function of TSA.

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“…p21 inhibits cyclin-dependent kinase and arrests the cell cycle from G1 to S [ 44 ]. p53 also regulates the expression of ER-related genes, such as Gadd45-α, p48-XPE, and DNA polymerase [ 45 ]. Gadd45-α binds to UVB-induced DNA damage lesions and recruits DNA repair proteins [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Regulation of p53 Activity by (+)-Epiloliolide Isolated from Ulva lactuca

et al. 2021

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Ulva lactuca (U. lactuca) is a green alga distributed worldwide and used as a food and cosmetic material. In our previous study, we determined the effects of U. lactuca methanol extracts on the UVB-induced DNA repair. In the present study, we fractionated U. lactuca methanol extracts to identify the effective compound for the DNA repair. MTT assay demonstrated that (+)-epiloliolide showed no cytotoxicity up to 100 μM in BJ-5ta human dermal fibroblast. Upon no treatment, exposure to UVB 400 J/m2 decreased cell viability by 45%, whereas (+)-epiloliolide treatment for 24 h after UVB exposure significantly increased the cell viability. In GO and GESA analysis, a number of differentially expressed genes were uniquely expressed in (+)-epiloliolide treated cells, which were enriched in the p53 signaling pathway and excision repair. Immunofluorescence demonstrated that (+)-epiloliolide increased the nuclear localization of p53. Comet assay demonstrated that (+)-epiloliolide decreased tail moment increased by UVB. Western blot analysis demonstrated that (+)-epiloliolide decreased the levels of p-p53, p21, Bax, and Bim, but increased that of Bcl-2. Reverse transcription PCR (RT-PCR) demonstrated that (+)-epiloliolide decreased the levels of MMP 1, 9, and 13, but increased that of COL1A1. These results suggest that (+)-epiloliolide regulates p53 activity and has protective effects against UVB.

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“…Interestingly, this endothelium defender (P53) [14] has been shown to be a direct target of the unfolded protein response (UPR) [21,22]. UPR acts to restore impaired functions of damaged tissues [23], including the lungs [24,25] and affects P53 levels in a positive manner.…”

mentioning

confidence: 99%