Profilin-1; a novel regulator of DNA damage response and repair machinery in keratinocytes

Lee, Changjin; Yoon, Min-Ji; Kim, Dong Hyun; Kim, Tae Uk; Kang, Youn‐Jung

doi:10.1007/s11033-021-06210-6

Cited by 6 publications

(2 citation statements)

References 49 publications

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“…Yet, this does not rule out other direct effects of profilin1 on the actin cytoskeleton, as it has been shown to interact with formins, Ena/Vasp, and WAVE ( 45 ). However, cell type–dependent differences in function likely exist, as profilin1-deficient keratinocytes demonstrate the failure to repair dsDNA breaks ( 46 ), which similarly may induce our mutant cells to continue through the cell cycle, as they are unable to return to the quiescent state.…”

Section: Discussionmentioning

confidence: 99%

Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases

Tian,

Pedigo,

et al. 2023

Journal of Clinical Investigation

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The progression of proteinuric kidney diseases is associated with podocyte loss, but the mechanisms underlying this process remain unclear. Podocytes reenter the cell cycle to repair double-stranded DNA breaks. However, unsuccessful repair can result in podocytes crossing the G 1 /S checkpoint and undergoing abortive cytokinesis. In this study, we identified Pfn1 as indispensable in maintaining glomerular integrity — its tissue-specific loss in mouse podocytes resulted in severe proteinuria and kidney failure. Our results suggest that this phenotype is due to podocyte mitotic catastrophe (MC), characterized histologically and ultrastructurally by abundant multinucleated cells, irregular nuclei, and mitotic spindles. Podocyte cell cycle reentry was identified using FUCCI2aR mice, and we observed altered expression of cell-cycle associated proteins, such as p21, p53, cyclin B1, and cyclin D1. Podocyte-specific translating ribosome affinity purification and RNA-Seq revealed the downregulation of ribosomal RNA-processing 8 ( Rrp8 ). Overexpression of Rrp8 in Pfn1- KO podocytes partially rescued the phenotype in vitro. Clinical and ultrastructural tomographic analysis of patients with diverse proteinuric kidney diseases further validated the presence of MC podocytes and reduction in podocyte PFN1 expression within kidney tissues. These results suggest that profilin1 is essential in regulating the podocyte cell cycle and its disruption leads to MC and subsequent podocyte loss.

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Section: Discussionmentioning

confidence: 99%

Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases

Tian,

Pedigo,

et al. 2023

Journal of Clinical Investigation

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“…PFN1 deletion accelerates DNA damage-mediated apoptosis due to the phosphorylation inactivation and Akt activation. 14 However, the predisposing factors of DN remain unclear and the molecular mechanisms of PFN1 in DN are also largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Profilin1 Promotes Renal Tubular Epithelial Cell Apoptosis in Diabetic Nephropathy Through the Hedgehog Signaling Pathway

Mai¹,

He²,

Chen³

et al. 2023

DMSO

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Background Profilin-1 (PFN1) regulates the dynamic balance of actin and plays an important role in cell functions as a hub protein in signaling molecule interaction networks. Dysregulation of PFN1 is related to pathologic kidney diseases. Diabetic nephropathy (DN) was recently reported as an inflammatory disorder, however, the molecular mechanisms of PFN1 in DN remain unclear. Therefore, the present study was conducted to explore the molecular and bioinformatic characteristics of PFN1 in DN. Methods Bioinformatics analyses were performed on the chip of database in DN kidney tissues. A cellular model of DN was established in human renal tubular epithelial cells (HK-2) induced by high glucose. The PFN1 gene was overexpressed or knocked-down to investigate its function in DN. Flow cytometry was used to detect cell proliferation and apoptosis. PFN1 and proteins in the related signaling pathways were evaluated by Western blotting. Results The expression of PFN1 was significantly increased in DN kidney tissues ( P < 0.001) and was correlated with a high apoptosis-associated score (Pearson’s correlation = 0.664) and cellular senescence-associated score (Pearson’s correlation = 0.703). PFN1 protein was mainly located in cytoplasm. Overexpression of PFN1 promoted apoptosis and blocked the proliferation of HK-2 cells treated with high levels of glucose. Knockdown of PFN1 led to the opposite effects. Additionally, we found that PFN1 was correlated with the inactivation of the Hedgehog signaling pathway in HK-2 cells treated with high levels of glucose. Conclusion PFN1 might play an integral role in the regulation of cell proliferation and apoptosis during DN development by activating the Hedgehog signaling pathway. This study provided molecular and bioinformatic characterizations of PFN1, and contributed to the understanding of the molecular mechanisms leading to DN.

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Proteomics in Patients with Fibromyalgia Syndrome: A Systematic Review of Observational Studies

Gkouvi,

Tsiogkas,

Bogdanos

et al. 2024

Curr Pain Headache Rep

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Purpose of Review Fibromyalgia syndrome (FMS) is a disease of unknown pathophysiology, with the diagnosis being based on a set of clinical criteria. Proteomic analysis can provide significant biological information for the pathophysiology of the disease but may also reveal biomarkers for diagnosis or therapeutic targets. The present systematic review aims to synthesize the evidence regarding the proteome of adult patients with FMS using data from observational studies. Recent Findings An extensive literature search was conducted in MEDLINE/PubMed, CENTRAL, and clinicaltrials.gov from inception until November 2022. The study protocol was published in OSF. Two independent reviewers evaluated the studies and extracted data. The quality of studies was assessed using the modified Newcastle–Ottawa scale adjusted for proteomic research. Ten studies fulfilled the protocol criteria, identifying 3328 proteins, 145 of which were differentially expressed among patients with FMS against controls. The proteins were identified in plasma, serum, cerebrospinal fluid, and saliva samples. The control groups included healthy individuals and patients with pain (inflammatory and non-inflammatory). Summary The most important proteins identified involved transferrin, α-, β-, and γ-fibrinogen chains, profilin-1, transaldolase, PGAM1, apolipoprotein-C3, complement C4A and C1QC, immunoglobin parts, and acute phase reactants. Weak correlations were observed between proteins and pain sensation, or quality of life scales, apart from the association of transferrin and a2-macroglobulin with moderate-to-severe pain sensation. The quality of included studies was moderate-to-good. FMS appears to be related to protein dysregulation in the complement and coagulation cascades and the metabolism of iron. Several proteins may be dysregulated due to the excessive oxidative stress response.

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Profilin-1; a novel regulator of DNA damage response and repair machinery in keratinocytes

Cited by 6 publications

References 49 publications

Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases

Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases

Profilin1 Promotes Renal Tubular Epithelial Cell Apoptosis in Diabetic Nephropathy Through the Hedgehog Signaling Pathway

Proteomics in Patients with Fibromyalgia Syndrome: A Systematic Review of Observational Studies

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