Biology subjects

von Muhlinen, N.

Publications and source records attributed to von Muhlinen, N..

5 recordsLinked to original sources

bioRxiv2026

Senescence-inhibitory Δ133p53α counteracts accelerated ageing and mortality

Research on progeria not only contributes to treatments for the disease but also enhances our understanding of physiological ageing1. Mouse models of progeria recapitulate pathological ageing phenotypes seen in patients, including cardiovascular defects, increased cellular senescence, systemic inflammation, DNA damage accumulation, and shortened lifespan2. In cultured cells from Hutchinson-Gilford progeria syndrome (HGPS) patients, the human p53 isoform {Delta}133p53 was previously shown to inhibit p53-mediated cellular senescence, proinflammatory IL-6 production, and DNA damage accumulation, and to extend cellular replicative lifespan3. Here we show that, in a heterozygous HGPS mouse model4, transgenic expression of {Delta}133p53 reproduces these in vitro-observed effects across multiple organs in vivo and extends median lifespan by 11% (387 versus 349 days, P = 0.0379). In the aorta and skin, {Delta}133p53 abrogates progeria-characteristic pathological changes and preserves tissue integrity. Our data further suggest that {Delta}133p53 may promote a broad spectrum of ageing-counteracting mechanisms, including bone homeostasis, metabolic fitness, antioxidant defense, youthful epigenome, and tissue stemness. Together with the anti-inflammatory and tissue-preserving effects of {Delta}133p53 in naturally aged mice and its age-associated downregulation in human tissues, this study suggests that {Delta}133p53-based therapeutic strategies may be applicable not only to HGPS but also as broader interventions for preventing or delaying ageing.

physiology↗

bioRxiv2025

Pharmacologic activation of Δ133p53α reduces cellular senescence in progeria patients-derived cells

BackgroundPatients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, have been developed, further efforts to explore mechanistically distinct and complementary strategies are still critical to better treatment regimens. We previously showed that lentiviral vector-driven expression of {Delta}133p53, a natural inhibitory isoform of p53, rescued HGPS patients-derived fibroblasts from early entry into cellular senescence, which is a downstream event of progerin-induced DNA damage. We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate {Delta}133p53 protein levels. MethodsTo investigate whether celastrol and ADZ1981 upregulate endogenous {Delta}133p53 in HGPS-derived fibroblasts and reduce their senescence-associated phenotypes, we performed western blot assays ({Delta}133p53, progerin, and p21WAF1, which mediates p53-induced senescence and is inhibited by {Delta}133p53), senescence-associated {beta}-galactosidase (SA-{beta}-gal) staining, enzyme-linked immunosorbent assay (IL-6, which is a proinflammatory cytokine secreted from senescent cells), and qRT-PCR assays (p21WAF1 and IL-6). ResultsTreatment with celastrol (0.1 {micro}M for 24 h) or AZD1981 (10 {micro}M for 24 h) reproducibly increased {Delta}133p53 expression and decreased p21WAF1 expression in two strains of fibroblasts derived from HGPS patients. These compounds reduced the percentage of SA-{beta}-gal-positive senescent cells and the secretion of IL-6 into culture medium in both of these fibroblast strains, irrespective of their different basal levels of senescence and IL-6 secretion. These compounds had no effect on the level of progerin. ConclusionCelastrol and ADZ1981 upregulate endogenous {Delta}133p53 and, reproducing the effects of its vector-driven expression, inhibit cellular senescence and IL-6 secretion in HGPS-derived fibroblasts. Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which {Delta}133p53-regulated senescence plays a role.

cell biology↗

bioRxiv2025

SRSF3 knockdown-induced cellular senescence as a possible therapeutic strategy for non-small cell lung cancer

Tyrosine kinase (TK) inhibitors improve clinical outcomes in non-small cell lung cancer (NSCLC) with targetable mutations. However, such NSCLC cases only consist of about 50% in the western populations. This study, for the first time in NSCLC cells including those without a targetable TK mutation, explores a tumor-suppressive activity of siRNA knockdown of a splicing factor SRSF3, which was reportedly effective in other cancer cell types. The knockdown of SRSF3 increased cellular senescence, indicated by senescence-associated {beta}-galactosidase activity and reduced cell proliferation, in all NSCLC cell lines examined, including A549 (no TK mutation; TP53 wild-type), NCI-H1975 (EGFR L858R/T790M; TP53 R273H mutant), NCI-H322 (no TK mutation; TP53 R248L mutant) and NCI-H596 (no TK mutation; TP53 G245C mutant). An increase in apoptotic cleavage of caspase-3 and poly(ADP-ribose) polymerase was also observed in A549 cells. p53{beta}, a tumor-suppressive p53 isoform generated via alternative mRNA splicing, was upregulated by SRSF3 knockdown, as previously reported in normal fibroblasts. However, neither cellular senescence nor apoptosis was increased by overexpression of p53{beta}, suggesting no or minimum contribution of this p53 isoform to the tumor-suppressive activity of SRSF3 knockdown in NSCLC cells. Our gene expression assay indicated that the SRSF3 knockdown-induced senescence in NSCLC cells may be mediated by downregulation of TOP2A, UBE2C or ASPM, which are known to be oncogenic and are associated with poor patient prognosis. We also generated SRSF3 siRNA-encapsulating lipid nanoparticles as a future therapeutic tool. This study suggests a therapeutic strategy for NSCLC irrespective of the mutation status of TP53 and TK-encoding genes. SummaryKnockdown of a splicing factor SRSF3 increases cellular senescence in NSCLC cells including those with no targetable mutation of tyrosine kinases and thus may represent a novel therapeutic strategy for a hard-to-treat group of NSCLC.

cancer biology↗

bioRxiv2022

Acidovorax temperans polarizes T17 cells and skews neutrophil maturation to promote lung adenocarcinoma development

Dysbiosis, or changes within the microbiome, is a common feature of solid tumors, however whether this dysbiosis directly contributes to tumor development is largely unknown. We previously characterized the lung cancer microbiome and identified Acidovorax temperans as enriched in tumors. In this study, we instilled A. temperans in an animal model driven by mutant Kras and Tp53 alleles. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic genotype with increased cytokine signaling, with a global shift away from IL-1{beta} signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+ T cells which polarized to an IL-17A+ phenotype detectable in CD4+ and {gamma}{delta} populations. T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate dysbiosis promotes tumor growth by modulating inflammation.

cancer biology↗

bioRxiv2018

Microbiome-TP53 Gene Interaction in Human Lung Cancer

BackgroundLung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) and cancer cases (n=143), we conducted 16S rRNA bacterial gene sequencing, with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort.\n\nResultsOverall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma (SCC) specifically, a separate group of taxa were identified, in which Acidovorax was enriched in smokers (P =0.0013). Acidovorax temporans was identified by fluorescent in situ hybridization within tumor sections, and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD).\n\nConclusionsThe results of this comprehensive study show both a microbiome-gene and microbiome-exposure interactions in SCC lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can damage epithelial function, have a unique bacterial consortia which is higher in relative abundance in smoking-associated SCC. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.

cancer biology↗