Towards DNA-damage induced autophagy: A Boolean model of p53-induced cell fate mechanisms

Gupta, Shantanu; Silveira, Daner A.; Mombach, José C. M.

doi:10.1016/j.dnarep.2020.102971

Cited by 41 publications

(37 citation statements)

References 85 publications

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“…Our current study demonstrated that inhibiting Wip1 activity led to enhanced apoptosis and autophagy in ovarian granulosa cells. Consistent with previous studies, the p53 pathway activation in granulosa cells induced by WIP inhibition contributed to both cell death phenotypes [60]. The mTOR signal pathway, the negative regulator of autophagy, was significantly inhibited after downregulating WIP1, causing excessive autophagy in granulosa cells.…”

Section: Discussionsupporting

confidence: 90%

“…Bulavin's team demonstrated that Wip1 deficiency or downregulation could activate autophagy through the ATM-mTOR signaling pathway, suggesting modulating WIP1-related autophagy could help preventing atherosclerosis [43,44]. A recent study also demonstrated that Wip1 related p53 pathway controls the cell fate through regulating autophagy and apoptosis [60]. Our current study demonstrated that inhibiting Wip1 activity led to enhanced apoptosis and autophagy in ovarian granulosa cells.…”

Section: Discussionsupporting

confidence: 60%

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Regulation of Follicular Atresia by WIP1-Mediated Apoptosis and Autophagy

Zhou

Chen

et al. 2021

Preprint

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Female endocrine homeostasis and reproductive success depend on the number and quality of follicles. The follicle is the basic functional unit within mammalian ovaries. Excessive follicular atresia is responsible for the accelerated ovarian aging process. Therefore, exploring the molecular mechanism of follicle development and atresia is essential for protecting ovarian function. In this study, we interrogate the striking correlation between follicular atresia and wild-type p53-induced phosphatase 1 (WIP1) expression in mouse ovaries to understand how WIP1 phosphatase activity regulates follicle development. WIP1 is mainly expressed in granulosa cells of healthy growing follicles, and atretic follicles exhibit significantly weaker WIP1 expression compared with the healthy ones. Our in vivo study indicates that inhibition of WIP1 phosphatase activity causes endocrine disorder, fertility decline and decreased ovarian reserve by triggering excessive follicular atresia through promoting autophagy and apoptosis. By in vitro follicle culture, we determine that inhibiting the WIP1 activity impairs the follicle development, causing more follicular atresia and decreased oocyte quality. Besides, downregulating WIP1 expression in granulosa cells in vitro also promotes apoptosis and autophagy via WIP1-p53 and WIP1-mTOR signal pathway. Our findings from the in vitro and in vivo experiments revealed that appropriate Wip1 expression is required for follicle development. Downregulation of WIP1 expression accelerates follicle atresia via WIP1-p53 and WIP1-mTOR signal pathway related apoptosis and autophagy. It is speculated that moderate up-regulation of WIP1 expression may help delaying the decline of ovarian reserve.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 60%

Regulation of Follicular Atresia by WIP1-Mediated Apoptosis and Autophagy

Zhou

Chen

et al. 2021

Preprint

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“…Recently, we published a model about the dynamics of the regulatory cores of SNAIL1 and ZEB1 during TGF-βinduced EMT using a logical computational approach [14] based on the experimental work by Zhang et al [8]. The logical method is recognized as a valuable tool to study biological regulatory processes [15][16][17][18][19][20][21][22][23][24]. Our analysis indicated testable predictions that could help improve strategies for breast cancer treatment.…”

Section: Introductionmentioning

confidence: 79%

Systems biology approach suggests new miRNAs as phenotypic stability factors in the epithelial–mesenchymal transition

Silveira

Gupta

Mombach

2020

J. R. Soc. Interface.

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The epithelial–mesenchymal transition (EMT) is a cellular programme on which epithelial cells undergo a phenotypic transition to mesenchymal ones acquiring metastatic properties such as mobility and invasion. TGF-β signalling can promote the EMT process. However, the dynamics of the concentration response of TGF-β-induced EMT is not well explained. In this work, we propose a logical model of TGF-β dose dependence of EMT in MCF10A breast cells. The model outcomes agree with experimentally observed phenotypes for the wild-type and perturbed/mutated cases. As important findings of the model, it predicts the coexistence of more than one hybrid state and that the circuit between TWIST1 and miR-129 is involved in their stabilization. Thus, miR-129 should be considered as a phenotypic stability factor. The circuit TWIST1/miR-129 associates with ZEB1-mediated circuits involving miRNAs 200, 1199, 340, and the protein GRHL2 to stabilize the hybrid state. Additionally, we found a possible new autocrine mechanism composed of the circuit involving TGF-β, miR-200, and SNAIL1 that contributes to the stabilization of the mesenchymal state. Therefore, our work can extend our comprehension of TGF-β-induced EMT in MCF10A cells to potentially improve the strategies for breast cancer treatment.

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“…All these pathways were implicated in cancer cell growth and proliferation [31,32]. SLC17A9 mRNA expression reportedly correlated positively with a TP53 mutation that could modulate DNA damage response, RNA transport, and protein binding [33]. SLC17A9 silencing reportedly inhibited the viability of C2C12, COS1, and HEK293T cells.…”

Section: Discussionmentioning

confidence: 97%

SLC17A9 Is a Novel Prognostic Biomarker Correlated With Immune Infiltrates in Human Lung Adenocarcinoma and Lung Squamous Cell Carcinoma

Gao

Chen

et al. 2021

Preprint

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Background Overexpression of vesicular nucleotide transporter (SLC17A9) has been found in different types of cancers. Nonetheless, little is known about its influence on lung cancers including human lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Methods Integrative analysis of SLC17A9 and other solute carrier family 17 genes (SLC17A1-8) was performed in patients with LUAD and LUSC based on The Cancer Genome Atlas database. Real-time PCR, western blots, MTS assay, EdU assay, ATP production assays and cell cycle analysis were applied to determine the effect and mechanism of SLC17A9 knockdown in LUAD cells. Results Compared with normal tissue, two SLC17 genes (SLC17A5 and SLC17A9) exhibited a distinctly different expression pattern in LUAD and LUSC. The expression of SLC17A3/7/8/9 expression was significantly correlated with worse overall survival (p < 0.05) in LUAD. Conversely, SLC17A1/2/4/6/9 expression was correlated with poorer OS (p < 0.05) in LUSC. ROC analysis suggested that the area under the curve of most SLC17 family genes was higher than 0.5. Meanwhile, multiple types of genetic alterations in SLC17 family genes were observed in tumor samples. Gene set enrichment analysis GSEA and protein-protein interaction results revealed that oncogenic signaling pathways and biological regulation, metabolic process, hallmark of myc targets, DNA repair, coagulation and complement were linked to SLC17A9 upregulation. Moreover, SLC17A9 knockdown significantly inhibited cell proliferation and ATP levels by affecting Myc, MFN2, STAT3, Cytochrome C and P2X1 expression in A549 cells. Specifically, SLC17A9 expression correlated negatively with overall survival and positively with most LUSC immune cells. SLC17A9 expression has correlations with infiltrating levels of B cells, CD4 + T cells, M1 macrophages, natural killer cells, Th1, Th2, Tfh, Th17 and Treg cells, as well as PD-1, CTLA4, and LAG3 of T cell exhaustion in LUAD. Conclusions Together, SLC17A9 could potentially serve as a prognostic biomarker correlated with immune infiltrates in LUAD and LUSC.

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Towards DNA-damage induced autophagy: A Boolean model of p53-induced cell fate mechanisms

Cited by 41 publications

References 85 publications

Regulation of Follicular Atresia by WIP1-Mediated Apoptosis and Autophagy

Regulation of Follicular Atresia by WIP1-Mediated Apoptosis and Autophagy

Systems biology approach suggests new miRNAs as phenotypic stability factors in the epithelial–mesenchymal transition

SLC17A9 Is a Novel Prognostic Biomarker Correlated With Immune Infiltrates in Human Lung Adenocarcinoma and Lung Squamous Cell Carcinoma

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