Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice

Horiguchi, Michiko; Yoshida, Masahiro; Hirata, Koji; Furuyama, Kenichiro; Masui, Toshihiko; Üemoto, Shinji; Kawaguchi, Yoshiya

doi:10.1002/1873-3468.13504

Cited by 6 publications

(3 citation statements)

References 44 publications

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“…This may have caused a responsive miR-17-5p upregulation aimed at their negative regulation. A similar mechanism may be in place, albeit indirectly, for miR-16-5p and Pre-B-cell leukemia transcription factor 1 (PDX1), as PDX1 depletion is known to induce senescence [40] and impaired mitophagy [41]. Therefore, we suspect that the presence of active ATG5/7alt pathway elements in both control and knockout models caused a gradual pressure on the miR feedback circuitry, eventually tipping the balance toward miR upregulation, resulting in ATG5/7alt suppression, which in turn may have led to mitochondrial dysfunction and senescence.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Bioinformatics Identifies Key microRNA Players in ATG7-Deficient Lung Fibroblasts

Stojanović

Fuchs

Fiedler

et al. 2020

IJMS

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Background: Deficient autophagy has been recently implicated as a driver of pulmonary fibrosis, yet bioinformatics approaches to study this cellular process are lacking. Autophagy-related 5 and 7 (ATG5/ATG7) are critical elements of macro-autophagy. However, an alternative ATG5/ATG7-independent macro-autophagy pathway was recently discovered, its regulation being unknown. Using a bioinformatics proteome profiling analysis of ATG7-deficient human fibroblasts, we aimed to identify key microRNA (miR) regulators in autophagy. Method: We have generated ATG7-knockout MRC-5 fibroblasts and performed mass spectrometry to generate a large-scale proteomics dataset. We further quantified the interactions between various proteins combining bioinformatics molecular network reconstruction and functional enrichment analysis. The predicted key regulatory miRs were validated via quantitative polymerase chain reaction. Results: The functional enrichment analysis of the 26 deregulated proteins showed decreased cellular trafficking, increased mitophagy and senescence as the major overarching processes in ATG7-deficient lung fibroblasts. The 26 proteins reconstitute a protein interactome of 46 nodes and miR-regulated interactome of 834 nodes. The miR network shows three functional cluster modules around miR-16-5p, miR-17-5p and let-7a-5p related to multiple deregulated proteins. Confirming these results in a biological setting, serially passaged wild-type and autophagy-deficient fibroblasts displayed senescence-dependent expression profiles of miR-16-5p and miR-17-5p. Conclusions: We have developed a bioinformatics proteome profiling approach that successfully identifies biologically relevant miR regulators from a proteomics dataset of the ATG-7-deficient milieu in lung fibroblasts, and thus may be used to elucidate key molecular players in complex fibrotic pathological processes. The approach is not limited to a specific cell-type and disease, thus highlighting its high relevance in proteome and non-coding RNA research.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Bioinformatics Identifies Key microRNA Players in ATG7-Deficient Lung Fibroblasts

Stojanović

Fuchs

Fiedler

et al. 2020

IJMS

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“…PDX1 is also a key regulator of β-cell proliferation and differentiation. Loss of PDX1 led to mouse pancreatic agenesis 43 , while PDX1 deficiency in acinar was found to cause cell senescence 44 . Our results also showed that acute FAM3A repression and β cell-specific FAM3A gene knockout could impair pancreatic β-cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells

Yan

Chen

Zhang

et al. 2021

Exp Clin Endocrinol Diabetes

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FAM3A is a recently identified mitochondrial protein that stimulates pancreatic-duodenal homeobox 1 (PDX1) and insulin expressions by promoting ATP release in islet β cells. In this study, the role of intracellular ATP in FAM3A-induced PDX1 expression in pancreatic β cells was further examined. Acute FAM3A inhibition using siRNA transfection in mouse pancreatic islets significantly reduced PDX1 expression, impaired insulin secretion, and caused glucose intolerance in normal mice. In vitro, FAM3A overexpression elevated both intracellular and extracellular ATP contents and promoted PDX1 expression and insulin secretion. FAM3A-induced increase in cellular calcium (Ca2+) levels, PDX1 expression, and insulin secretion, while these were significantly repressed by inhibitors of P2 receptors or the L-type Ca2+ channels. FAM3A-induced PDX1 expression was abolished by a calmodulin inhibitor. Likewise, FAM3A-induced β-cell proliferation was also inhibited by a P2 receptor inhibitor and an L-type Ca2+ channels inhibitor. Both intracellular and extracellular ATP contributed to FAM3A-induced PDX1 expression, insulin secretion, and proliferation of pancreatic β cells.

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“…The exocrine pancreas is composed of acinar cells (>90%) which, under aging and stress, dedifferentiate and acquire an early pancreatic progenitor phenotype, concomitant with activation of the Ras-Mapk pathway and of a senescence program [ 90 ]. The dedifferentiated acinar cells were proliferation arrested by the acquisition of a senescent state, characterized by induction of p53, p21 Cip1 , p16 Ink4a , and SA-β-Gal [ 91 , 92 , 93 , 94 ].…”

Section: Cellular Senescence In β-Cells and Diabetesmentioning

confidence: 99%

Interaction between Autophagy and Senescence in Pancreatic Beta Cells

Hela,

Aguayo-Mazzucato

2023

Biology

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Aging leads to an increase in cellular stress due to the fragility of the organism and the inability to cope with it. In this setting, there is a higher chance of developing different cardiometabolic diseases like diabetes. Cellular senescence and autophagy, both hallmarks of aging and stress-coping mechanisms, have gained increased attention for their role in the pathophysiology of diabetes. Studies show that impairing senescence dampens and even prevents diabetes while the role of autophagy is more contradictory, implying a context- and disease-stage-dependent effect. Reports show conflicting data about the effect of autophagy on senescence while the knowledge about this interaction in beta cells remains scarce. Elucidating this interaction between autophagy and senescence in pancreatic beta cells will lead to an identification of their respective roles and the extent of the effect each mechanism has on beta cells and open new horizons for developing novel therapeutic agents. To help illuminate this relationship we will review the latest findings of cellular senescence and autophagy with a special emphasis on pancreatic beta cells and diabetes.

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Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice

Cited by 6 publications

References 44 publications

Comprehensive Bioinformatics Identifies Key microRNA Players in ATG7-Deficient Lung Fibroblasts

Comprehensive Bioinformatics Identifies Key microRNA Players in ATG7-Deficient Lung Fibroblasts

Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells

Interaction between Autophagy and Senescence in Pancreatic Beta Cells

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