[miR-342-3p Promotes the Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma Cells by Targeted Inhibition of PPM1E]. / miR-342-3p通过靶向抑制PPM1E促进肾透明细胞癌细胞的增殖、迁移和侵袭.

Objective: To explore the effects of microRNA-342-3p/Mg2+Mn2+-dependent protein phosphatase 1E (miR-342-3p/PPM1E) on the proliferation, migration, and invasion of clear cell renal cell carcinoma (ccRCC) cells. Methods: The gene chips GSE12105, GSE23085, GSE66271, and GSE66270 were searched, and the relationship between miR-342-3p, PPM1E, and the clinical malignant phenotypes of ccRCC was analyzed. ACHN and 769-P cells were transfected with miR-342-3p inhibitor. The effects of miR-342-3p on cell proliferation, migration, and invasion were examined. ACHN cell line with stable and high expression of miR-342-3p was constructed, and the tumorigenicity of the cell line in BALB/c nude mice was observed. The targeted relationship between miR-342-3p and PPM1E was verified by dual-luciferase reporter gene assay. The cells were transfected with miR-342-3p mimic and pcDNA-PPM1E plasmids to observe whether PPM1E could reverse the effects of miR-342-3p overexpression on the proliferation, migration, and invasion of the cells. Results: The expression of miR-342-3p was upregulated in ccRCC, and there were significant differences among patients with tumors of different T stages and G stages and those with different prognoses (P<0.05). The overall survival in the miR-342-3p high-expression group was significantly shorter than that in the low-expression group (P<0.05). Compared with those in the miR-NC group, the miR-342-3p level was significantly downregulated in the inhibitor group, and the cell proliferation ability and the numbers of migrating and invading cells were also significantly decreased (P<0.05). Compared with the miR-NC group, miR-342-3p group had significantly increased volume and mass of tumor tissues and miR-342-3p level, but significantly decreased level of PPM1E mRNA (P<0.05). The expression of PPM1E was downregulated in ccRCC, and there were significant differences among patients with tumors of different M stages, N stages, and G stages, and different recurrence statuses (P<0.05). The miR-342-3p could inhibit the expression of PPM1E in a targeted way. Compared with the miR-NC group, the miR-342-3p group had significantly increased cell proliferation ability and increased numbers of migrating and invading cells (P<0.05). However, PPM1E could reverse the promotion effect of miR-342-3p mimic on ccRCC cells (P<0.05). Conclusion: The miR-342-3p can inhibit PPM1E expression in a targeted way, and thus promotes the proliferation, migration, and invasion of ccRCC cells.

SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells.

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

Identification of PP2Cs in six rosaceae species highlights RcPP2C24 as a negative regulator in rose drought tolerance.

Drought is a major environmental stress that limits plant growth, so it's important to identify drought-responsive genes to understand the mechanism of drought response and breed drought-tolerant roses. Protein phosphatase 2C (PP2C) plays a crucial role in plant abiotic stress response. In this study, we identified 412 putative PP2Cs from six Rosaceae species. These genes were divided into twelve clades, with clade A containing the largest number of PP2Cs (14.1%). Clade A PP2Cs are known for their important role in ABA-mediated drought stress response; therefore, the analysis focused on these specific genes. Conserved motif analysis revealed that clade A PP2Cs in these six Rosaceae species shared conserved C-terminal catalytic domains. Collinearity analysis indicated that segmental duplication events played a significant role in the evolution of clade A PP2Cs in Rosaceae. Analysis of the expression of 11 clade A RcPP2Cs showed that approximately 60% of these genes responded to drought, high temperature, and salt stress. Among them, RcPP2C24 exhibited the highest responsiveness to both drought and ABA. Furthermore, overexpression of RcPP2C24 significantly reduced drought tolerance in transgenic tobacco by increasing stomatal aperture after exposure to drought stress. The transient overexpression of RcPP2C24 weakened the dehydration tolerance of rose petal discs, while its silencing increased their dehydration tolerance. In summary, our study identified PP2Cs in six Rosaceae species and highlighted the negative role of RcPP2C24 on rose's drought tolerance by inhibiting stomatal closure. Our findings provide valuable insights into understanding the mechanism behind rose's response to drought.

Rapeseed PP2C37 Interacts with PYR/PYL Abscisic Acid Receptors and Negatively Regulates Drought Tolerance.

Global water deficit is a severe abiotic stress threatening the yielding and quality of crops. Abscisic acid (ABA) is a phytohormone that mediates drought tolerance. Protein kinases and phosphatases function as molecular switches in eukaryotes. Protein phosphatases type 2C (PP2Cs) are a major family that play essential roles in ABA signaling and stress responses. However, the role and underlying mechanism of PP2C in rapeseed (Brassica napus L.) mediating drought response has not been reported yet. Here, we characterized a PP2C family member, BnaPP2C37, and its expression level was highly induced by ABA and dehydration treatments. It negatively regulates drought tolerance in rapeseed. We further identified that BnaPP2C37 interacted with multiple PYR/PYL receptors and a drought regulator BnaCPK5 (calcium-dependent protein kinase 5) through yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. Specifically, BnaPYL1 and BnaPYL9 repress BnaPP2C37 phosphatase activity. Moreover, the pull-down assay and phosphatase assays show BnaPP2C37 interacts with BnaCPK5 to dephosphorylate BnaCPK5 and its downstream BnaABF3. Furthermore, a dual-luciferase assay revealed BnaPP2C37 transcript level was enhanced by BnaABF3 and BnaABF4, forming a negative feedback regulation to ABA response. In summary, we identified that BnaPP2C37 functions negatively in drought tolerance of rapeseed, and its phosphatase activity is repressed by BnaPYL1/9 whereas its transcriptional level is upregulated by BnaABF3/4.

Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer.

Clonal hematopoiesis (CH) driven by mutations in the DNA damage response (DDR) pathway is frequent in patients with cancer and is associated with a higher risk of therapy-related myeloid neoplasms (t-MNs). Here, we analyzed 423 serial whole blood and plasma samples from 103 patients with relapsed high-grade ovarian cancer receiving carboplatin, poly(ADP-ribose) polymerase inhibitor (PARPi) and heat shock protein 90 inhibitor (HSP90i) treatment within the phase II EUDARIO trial using error-corrected sequencing of 72 genes. DDR-driven CH was detected in 35% of patients and was associated with longer duration of prior PARPi treatment. TP53- and PPM1D-mutated clones exhibited substantially higher clonal expansion rates than DNMT3A- or TET2-mutated clones during treatment. Expansion of DDR clones correlated with HSP90i exposure across the three study arms and was partially abrogated by the presence of germline mutations related to homologous recombination deficiency. Single-cell DNA sequencing of selected samples revealed clonal exclusivity of DDR mutations, and identified DDR-mutated clones as the origin of t-MN in two investigated cases. Together, these results provide unique insights into the architecture and the preferential selection of DDR-mutated hematopoietic clones under intense DNA-damaging treatment. Specifically, PARPi and HSP90i therapies pose an independent risk for the expansion of DDR-CH in a dose-dependent manner.

Clonal hematopoiesis-derived therapy-related myeloid neoplasms after autologous hematopoietic stem cell transplant for lymphoid and non-lymphoid disorders.

Therapy-related myeloid neoplasms (tMN) are complications of cytotoxic therapies. Risk of tMN is high in recipients of autologous hematopoietic stem cell transplantation (aHSCT). Acquisition of genomic mutations represents a key pathogenic driver but the origins, timing and dynamics, particularly in the context of preexisting or emergent clonal hematopoiesis (CH), have not been sufficiently clarified. We studied a cohort of 1507 patients undergoing aHSCT and a cohort of 263 patients who developed tMN without aHSCT to determine clinico-molecular features unique to post-aHSCT tMN. We show that tMN occurs in up to 2.3% of patients at median of 2.6 years post-AHSCT. Age ≥ 60 years, male sex, radiotherapy, high treatment burden ( ≥ 3 lines of chemotherapy), and graft cellularity increased the risk of tMN. Time to evolution and overall survival were shorter in post-aHSCT tMN vs. other tMN, and the earlier group's mutational pattern was enriched in PPM1D and TP53 lesions. Preexisting CH increased the risk of adverse outcomes including post-aHSCT tMN. Particularly, antecedent lesions affecting PPM1D and TP53 predicted tMN evolution post-transplant. Notably, CH-derived tMN had worse outcomes than non CH-derived tMN. As such, screening for CH before aHSCT may inform individual patients' prognostic outcomes and influence their prospective treatment plans. Presented in part as an oral abstract at the 2022 American Society of Hematology Annual Meeting, New Orleans, LA, 2022.

Clonal Hematopoiesis and Therapy-Related Myeloid Neoplasms After Autologous Transplant for Hodgkin Lymphoma.

PURPOSE: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell transplantation (aPBSCT) for Hodgkin lymphoma (HL). Although previous studies have reported an association between clonal hematopoiesis (CH) in the infused PBSC product and subsequent post-aPBSCT risk of t-MN in patients with non-HL, information about patients with HL treated with aPBSCT is not available. METHODS: We constructed a retrospective cohort of 321 patients with HL transplanted at a median age of 34 years (range, 18-71). Targeted DNA sequencing of PBSC products performed for CH-associated or myeloid malignancy-associated genes identified pathogenic mutations in these patients. RESULTS: CH was identified in the PBSC product of 46 patients (14.3%) with most prominent representation of DNMT3A (n = 25), PPM1D (n = 7), TET2 (n = 7), and TP53 (n = 5) mutations. Presence of CH in the PBSC product was an independent predictor of t-MN (adjusted hazard ratio [aHR], 4.50 [95% CI, 1.54 to 13.19]). Notably all patients with TP53 mutations in the PBSC product developed t-MN, whereas none of the patients with DNMT3A mutations alone (without co-occurring TP53 or PPM1D mutations) did. Presence of TP53 and/or PPM1D mutations was associated with a 7.29-fold higher hazard of t-MN when compared with individuals carrying no CH mutations (95% CI, 1.72 to 30.94). The presence of TP53 and/or PPM1D mutations was also associated with a 4.17-fold higher hazard of nonrelapse mortality (95% CI, 1.25 to 13.87). There was no association between CH and relapse-related mortality. CONCLUSION: The presence of TP53 and/or PPM1D mutations in the PBSC product increases the risk of post-aPBSCT t-MN and nonrelapse mortality among patients with HL and may support alternative therapeutic strategies.

miR-743b-3p promotes hepatic lipogenesis via branched-chain amino acids (BCAA) metabolism by targeting PPM1K in aged mice.

BACKGROUND: Lipid metabolism disorders appear to play an important role in the ageing process, thus understanding the cellular and molecular mechanisms underlying the association of ageing with elevated vulnerability to lipid metabolism related diseases is crucial towards promoting quality of life in old age. MicroRNAs (miRNAs) have emerged as crucial regulators of lipid metabolism, and some miRNAs have key roles in ageing. METHODS: In this study, we investigated changes in liver lipid metabolism of ageing mice and the mechanisms of the altered expression of miRNAs in the ageing liver which contributes to the age-dependent increase in lipid synthesis. Here we found that miR-743b-3p was higher expressed in the liver tissues of ageing mice through the small RNA sequencing and bioinformatics analysis, and its target PPM1K was predicted and confirmed the target relationship of miR-743b-3p with PPM1K in the aged mouse liver tissues and the cultured senescent hepatocytes in vitro. Moreover, using the transfected miR-743b-3p mimics/inhibitors into the senescent hepatocyte AML12. RESULTS: We found that miR-743b-3p inhibition reversed the hepatocyte senescence, and finally decreased the expression of genes involved in lipid synthesis(Chrebp, Fabp4, Acly and Pparγ) through increasing the target gene expression of PPM1K which regulated the expression of branched-chain amino acids (BCAA) metabolism-related genes (Bckdhα, Bckdk, Bcat2, Dbt). CONCLUSIONS: These results identify that age-induced expression of miR-743b-3p inhibits its target PPM1K which induces BCAA metabolic disorder and regulates hepatocyte lipid accumulation during ageing.

Generation of a PPM1A-deficient human induced pluripotent stem cell line using CRISPR-Cas9 technology.

PPM1A is a member of the serine/threonine protein phosphatase family. It can bind to a variety of proteins to dephosphorylate them, and extensively regulates many life activities such as cell growth, cell stress, immune response, and tumor formation. Here we constructed a human induced pluripotent stem cell (hiPSC) line with knockout of PPM1A using CRISPR/Cas9-mediated gene targeting. This cell line exhibits normal karyotype, pluripotency, and trilineage differentiation potential, which could provide a useful cellular resource for exploring the mechanism of PPM1A in regulating downstream signaling pathways and explore the application of PPM1A in anti-tumor and anti-infection.

SlbHLH1 mediates ABA treatment-retarded chilling injury by repressing SlPP2C29 in tomato fruit.

Low-temperature storage can facilitate to the preservation of postharvest fruits. However, tomato fruit are vulnerable to chilling injury (CI) throughout refrigerated storage, resulting in economic losses. Abscisic acid (ABA) treatment weakened the CI progression in tomato fruit. Protein phosphatase 2 C 29 (SlPP2C29) acted as the negative regulator in the ABA-enhanced chilling tolerance. The gene expression of SlPP2C29 and activity of PP2C were down regulated by ABA treatment. Furthermore, SlPP2C29 was shown to be the negative downstream messenger in the ABA-alleviated oxidative damage. Moreover, basic helix-loop-helix 1 (SlbHLH1) bound to the E-box element within SlPP2C29 promoter, and negatively modulated its expression. SlbHLH1 mediated the ABA-boosted chilling tolerance. It turned out that SlbHLH1 was the positive modulator involved in the ABA-inhibited SlPP2C29 expression and PP2C activity. SlbHLH1 was furtherly found to work as the positive regulator in the ABA-lowered oxidative damage. Thus, SlbHLH1 alleviated the CI severity by repressing SlPP2C29 under ABA treatment in tomato fruit.

Genome-wide identification and characterization of protein phosphatase 2C (PP2C) gene family in sunflower (Helianthus annuus L.) and their expression profiles in response to multiple abiotic stresses.

Plant protein phosphatase 2C (PP2C) plays vital roles in responding to various stresses, stimulating growth factors, phytohormones, and metabolic activities in many important plant species. However, the PP2C gene family has not been investigated in the economically valuable plant species sunflower (Helianthus annuus L.). This study used comprehensive bioinformatics tools to identify and characterize the PP2C gene family members in the sunflower genome (H. annuus r1.2). Additionally, we analyzed the expression profiles of these genes using RNA-seq data under four different stress conditions in both leaf and root tissues. A total of 121 PP2C genes were identified in the sunflower genome distributed unevenly across the 17 chromosomes, all containing the Type-2C phosphatase domain. HanPP2C genes are divided into 15 subgroups (A-L) based on phylogenetic tree analysis. Analyses of conserved domains, gene structures, and motifs revealed higher structural and functional similarities within various subgroups. Gene duplication and collinearity analysis showed that among the 53 HanPP2C gene pairs, 48 demonstrated segmental duplications under strong purifying selection pressure, with only five gene pairs showing tandem duplications. The abundant segmental duplication was observed compared to tandem duplication, which was the major factor underlying the dispersion of the PP2C gene family in sunflowers. Most HanPP2C proteins were localized in the nucleus, cytoplasm, and chloroplast. Among the 121 HanPP2C genes, we identified 71 miRNAs targeting 86 HanPP2C genes involved in plant developmental processes and response to abiotic stresses. By analyzing cis-elements, we identified 63 cis-regulatory elements in the promoter regions of HanPP2C genes associated with light responsiveness, tissue-specificity, phytohormone, and stress responses. Based on RNA-seq data from two sunflower tissues (leaf and root), 47 HanPP2C genes exhibited varying expression levels in leaf tissue, while 49 HanPP2C genes showed differential expression patterns in root tissue across all stress conditions. Transcriptome profiling revealed that nine HanPP2C genes (HanPP2C12, HanPP2C36, HanPP2C38, HanPP2C47, HanPP2C48, HanPP2C53, HanPP2C54, HanPP2C59, and HanPP2C73) exhibited higher expression in leaf tissue, and five HanPP2C genes (HanPP2C13, HanPP2C47, HanPP2C48, HanPP2C54, and HanPP2C95) showed enhanced expression in root tissue in response to the four stress treatments, compared to the control conditions. These results suggest that these HanPP2C genes may be potential candidates for conferring tolerance to multiple stresses and further detailed characterization to elucidate their functions. From these candidates, 3D structures were predicted for six HanPP2C proteins (HanPP2C47, HanPP2C48, HanPP2C53, HanPP2C54, HanPP2C59, and HanPP2C73), which provided satisfactory models. Our findings provide valuable insights into the PP2C gene family in the sunflower genome, which could play a crucial role in responding to various stresses. This information can be exploited in sunflower breeding programs to develop improved cultivars with increased abiotic stress tolerance.

PPM1G regulates hepatic ischemia/reperfusion injury through STING-mediated inflammatory pathways in macrophages.

BACKGROUND: Ischemia/reperfusion injury (IRI) is generally unavoidable following liver transplantation. Here, we investigated the role of protein phosphatase, Mg2+ /Mn2+ dependent 1G (PPM1G) in hepatic IRI. METHODS: Hepatic IRI was mimicked by employing a hypoxia/reperfusion (H/R) model in RAW 264.7 cells and a 70% warm ischemia model in C57BL/6 mice, respectively. In vitro, expression changes of tumor necrosis factor-α and interleukin were detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and enzyme-linked immunosorbent assay. The protein expressions of PPM1G and the stimulator of interferon genes (STING) pathway components were analyzed by western blot. Interaction between PPM1G and STING was verified by coimmunoprecipitation (CO-IP). Immunofluorescence was applied for detection of p-IRF3. Flow cytometry, qRT-PCR and western blot were utilized to analyze markers of macrophage polarization. In vivo, histological analyses of mice liver were carried out by TUNEL and H&E staining. Changes in serum aminotransferases were also detected. RESULTS: Following H/R intervention, a steady decline in PPM1G along with an increase in inflammatory cytokines in vitro was observed. Addition of plasmid with PPM1G sequence limited the release of inflammatory cytokines and downregulated phosphorylation of STING. CO-IP validated the interaction between PPM1G and STING. Furthermore, inhibition of PPM1G with lentivirus enhanced phosphorylation of STING and its downstream components; meanwhile, p65, p38, and Jnk were also surged to phosphorylation. Expression of INOS and CD86 was surged, while CD206, Arg-1, and IL-10 were inhibited. In vivo, PPM1G inhibition further promoted liver damage, hepatocyte apoptosis, and transaminases release. Selective inhibition of STING with C-176 partially reversed the activation of STING pathway and inflammatory cytokines in vitro. M1 markers were also suppressed by C-176. In vivo, C-176 rescued liver damage and transaminase release caused by PPM1G inhibition. CONCLUSION: PPM1G suppresses hepatic IRI and macrophage M1 phenotype by repressing STING-mediated inflammatory pathways.

Phosphatase, Mg2+/Mn2+ dependent 1B regulates the hematopoietic stem cells homeostasis via the Wnt/ß-catenin signaling.

Hematopoietic stem cells (HSC) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance. How HSC maintain the balance between activation and quiescence remains largely unknown. Herein, we found that phosphatase, Mg2+/Mn2+ dependent 1B (Ppm1b) is required for the expansion of phenotypic HSC in vitro. By using a conditional knockout mouse model in which Ppm1b was specifically depleted in hematopoietic cells, we demonstrated that loss of Ppm1b impaired the HSC homeostasis and hematopoietic reconstitution. Ppm1b deficiency mice also exhibited B-cell leukocytopenia, which is due to the compromised commitment and proliferation of B-biased lymphoid progenitor cells from common lymphoid progenitors. With the aid of a small molecular inhibitor, we confirmed the roles of Ppm1b in adult hematopoiesis that phenocopied the effects with loss of Ppm1b. Furthermore, transcriptome profiling of Ppm1b-deficient HSC revealed the disruptive quiescence of HSC. Mechanistically, Ppm1b interacted with ß-catenin and mediated its dephosphorylation. Loss of Ppm1b led to the decrease in the active ß-catenin (non-phosphorylated) that interrupted the Wnt/ß-catenin signaling in HSC, which consequently suppressed HSC expansion. Together, our study identified an indispensable role for Ppm1b in regulating HSC homeostasis via the Wnt/ß-catenin pathway.

Modulation of YBX1-mediated PANoptosis inhibition by PPM1B and USP10 confers chemoresistance to oxaliplatin in gastric cancer.

Gastric cancer (GC) is a common malignant tumor of the digestive tract, and chemoresistance significantly impacts GC patients' prognosis. PANoptosis has been associated with oxaliplatin-induced cell death. However, the direct regulatory role of YBX1 in cellular chemoresistance through PANoptosis remains unclear. In this study, we investigated the impact of YBX1 on regulating PANoptosis and its influence on the resistance of gastric cancer cells to oxaliplatin. Through overexpression and silencing experiments, we assessed YBX1's effect on proliferation and PANoptosis regulation in gastric cancer cells. Additionally, we identified PPM1B and USP10 as interacting proteins with YBX1 and confirmed their influence on YBX1 molecular function and protein expression levels. Our results demonstrate that YBX1 suppresses PANoptosis, leading to enhanced resistance of gastric cancer cells to oxaliplatin. Furthermore, we found that PPM1B and USP10 play critical roles in regulating YBX1-mediated PANoptosis inhibition. PPM1B directly interacts with YBX1, causing dephosphorylation of YBX1 at serine 314 residue. This dephosphorylation process affects the deubiquitination of YBX1 mediated by USP10, resulting in decreased YBX1 protein expression levels and impacting PANoptosis and oxaliplatin resistance in gastric cancer cells. Additionally, we discovered that the 314th amino acid of YBX1 has a profound impact on its own protein expression abundance, thereby affecting the functionality of YBX1. In conclusion, our study reveals the significance of PPM1B-mediated dephosphorylation of YBX1 and USP10-mediated deubiquitination in regulating PANoptosis and sensitivity to oxaliplatin in gastric cancer cells. These findings offer a potential therapeutic strategy for patients with oxaliplatin-resistant gastric cancer.

Systemic inflammation and risk of Parkinson's disease: A prospective cohort study and genetic analysis.

BACKGROUND: Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. METHODS: Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. RESULTS: A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79-0.90, P = 4.23E-07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: -0.14, P = 6.31E-05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = -0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB, HNF4A, PPM1G, ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. CONCLUSIONS: Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials.

Correlation between changes in serum YKL-40, LXRs, PPM1A, and TGF-ß1 levels and airway remodeling and lung function in patients with bronchial asthma.

OBJECTIVE: This study investigates the correlation between serum levels of YKL-40, LXRs, PPM1A, and TGF-ß1 and airway remodeling and lung function in bronchial asthma patients. METHODS: The study involved 80 bronchial asthma patients and 92 healthy individuals. Serum cytokines, airway remodeling, and lung function markers were compared across mild, moderate, and severe asthma cases using high-resolution CT, t-tests, ANOVA, and Pearson correlation analysis. RESULTS: Asthmatic patients exhibited higher levels of serum YKL-40, LXRα, LXRß, TGF-ß1, airway wall thickness (T)/outer diameter (D), and WA% of total cross-sectional area compared to controls. Conversely, their serum PPM1A, Peak Expiratory Flow (PEF), and Forced Expiratory Volume in 1 s (FEV1) were lower. Serum YKL-40 and TGF-ß1 levels were positively correlated with T/D and WA%, and negatively correlated with PEF and FEV1. PPM1A levels were strongly associated with T/D, WA%, PEF, and FEV1. CONCLUSION: The severity of bronchial asthma is associated with increased serum levels of YKL-40, LXRα, LXRß, and TGF-ß1 and decreased PPM1A. The levels of YKL-40, PPM1A, and TGF-ß1 have a significant correlation with airway remodeling and lung function.

RBM10 regulates the tumorigenic potential of human cancer cells by modulating PPM1B and YBX1 activities.

RNA binding protein RBM10 participates in various RNA metabolism, and its decreased expression or loss of function by mutation has been identified in many human cancers. However, how its dysregulation contributes to human cancer pathogenesis remains to be determined. Here, we found that RBM10 expression was decreased in breast tumors, and breast cancer patients with low RBM10 expression presented poorer survival rates. RBM10 depletion in breast cancer cells significantly promotes the cellular proliferation and migration. We further demonstrated that RBM10 forms a triple complex with YBX1 and phosphatase 1B (PPM1B), in which PPM1B serves as the phosphatase of YBX1. RBM10 knock-down markedly attenuated association between YBX1 and PPM1B, leading to elevated levels of YBX1 phosphorylation and its nuclear translocation. Furthermore, cancer cells with RBM10 depletion had a significantly accelerated tumor growth in nude mice. Importantly, these enhanced tumorigenic phenotypes can be reversed by overexpression of PPM1B. Our findings provide the mechanistic bases for functional loss of RBM10 in promoting tumorigenicity, and are potentially useful in the development of combined therapeutic strategies for cancer patients with defective RBM10.

Overexpression of PPM1B inhibited chemoresistance to temozolomide and proliferation in glioma cells.

Protein phosphatase magnesium-dependent 1B (PPM1B) functions as IKKß phosphatases to terminate nuclear factor kappa B (NF-κB) signaling. NF-κB signaling was constitutively activated in glioma cells. At present, little is known about the role of PPM1B in glioma. In the current study, we found that the expression of PPM1B was reduced in glioma tissues and cells, and decreased expression of PPM1B was related to poor overall survival of patients. Overexpression of PPM1B inhibited the proliferation and promoted apoptosis of glioma cells. Moreover, PPM1B overexpression reduced the phosphorylation of IKKß and inhibited the nuclear localization of NF-κBp65. PDTC, an inhibitor of NF-κB signaling, reversed PPM1B-knockdown-induced cell proliferation. Furthermore, overexpression of PPM1B enhanced the sensitivity of glioma cells to temozolomide. In vivo experiments showed that overexpression of PPM1B could inhibit tumor growth, improve the survival rate of nude mice, and enhance the sensitivity to temozolomide. In conclusion, PPM1B suppressed glioma cell proliferation and the IKKß-NF-κB signaling pathway, and enhanced temozolomide sensitivity of glioma cells.

PPM1D activity promotes the replication stress caused by cyclin E1 overexpression.

Oncogene-induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and has been implicated in termination of the cell cycle checkpoint. Amplification of the PPM1D gene or frameshift mutations in its final exon promote tumorigenesis. Here, we show that PPM1D activity further increases the replication stress caused by overexpression of cyclin E1. In particular, we demonstrate that cells expressing a truncated mutant of PPM1D progress faster from G1 to S phase and fail to complete licensing of the replication origins. In addition, we show that transcription-replication collisions and replication fork slowing caused by CCNE1 overexpression are exaggerated in cells expressing the truncated PPM1D. Finally, replication speed and accumulation of focal DNA copy number alterations caused by induction of CCNE1 expression was rescued by pharmacological inhibition of PPM1D. We propose that increased activity of PPM1D suppresses the checkpoint function of p53 and thus promotes genome instability in cells expressing the CCNE1 oncogene.

A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.

Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.