BMB Reports最新文献

F-box and leucine-rich repeat protein 18 (FBXL18) is closely associated with cancer progression. However, its role in regulating the radioresistance of esophageal squamous cell carcinoma (ESCC) remains unclear. Radioresistant ESCC cells were developed using fractional doses of X-ray irradiation, and validated via cell counting kit-8 (CCK-8) assay. The sensitivity of these radioresistant cells to radiotherapy was also assessed using CCK-8. The expression levels of FBXL18 and Cyclin D1 (CCND1) were analyzed through Western blotting. RNA interference (RNAi) technology was employed to investigate whether silencing FBXL18 could reduce ESCC radioresistance and inhibit the AKT/CCND1 signaling pathway. Co-immunoprecipitation and Western blotting were used to evaluate the polyubiquitination of AKT. Radioresistant ESCC cells were successfully established, and FBXL18 expression was significantly elevated in these cells. Increased levels of phosphorylated AKT (p-AKT) and CCND1 were also observed. Silencing FBXL18 notably reduced the radioresistance of ESCC cells and decreased p-AKT and CCND1 expression levels. Also, FBXL18 was found to interact with AKT, promoting its K63-linked polyubiquitination, and activating the AKT/CCND1 signaling pathway. FBXL18 interacts with AKT and facilitates its K63-linked polyubiquitination, thereby activating AKT/CCND1 signaling while maintaining the radioresistance of ESCC cells.

Casein kinase 1 (CK1) enzymes, a family of serine/threoninespecific protein kinases, are remarkably conserved throughout evolution and exhibit diverse functionalities across eukaryotic species. While initially characterized by their role in casein (a type of milk protein) phosphorylation, subsequent investigations have unveiled their extensive involvement in fundamental biological processes, including cell division, maintenance of DNA integrity, programmed cell death, and the intricate regulation of gene transcription. Furthermore, CK1 significantly influences circadian rhythm mechanisms, highlighting its systemic regulatory importance. In mammals, multiple CK1 isoforms have been identified, each contributing to both physiological functions and various disease states. Dysregulation of CK1 activity is consistently associated with oncogenesis, where it promotes tumor cell proliferation, survival, metastasis, and resistance to therapeutic interventions. Emerging evidence also points to the critical relevance of CK1 in non-malignant conditions, such as neurodegenerative diseases, metabolic syndromes, and immune dysfunctions. In these conditions, CK1 often mediates pathogenic signaling through aberrant phosphorylation and the disruption of temporal gene expression. This review aims to re-examine the CK1 family as a versatile regulator that interacts with various pathological conditions, extending beyond its traditional classification as merely a signaling kinase. We provide an overview of the structural and functional properties of CK1 isoforms, summarize their relevance across a range of diseases, and explore novel possibilities for therapeutic interventions targeting this kinase family. Moreover, by reviewing the current understanding of CK1, we search for a new perspective on its role in maintaining cellular balance and its contribution to disease mechanisms, thereby proposing novel avenues for future research.

The CaMKIV-c-Fos-NFATc1 axis is established in osteoclastogenesis, but its role in osteoblasts is largely unexplored. We show that this axis suppresses osteoblast differentiation and bone formation. Silencing CaMKIV increased osteogenic gene expression and mineralization, whereas overexpressing c-Fos or NFATc1 reduced osteoblast activity. Mechanistically, CaMKIV binds c-Fos and inhibits its ubiquitination, stabilizing c-Fos and elevating NFATc1. NFATc1, in turn, impairs Runx2 acetylation by competing for PCAF, thereby attenuating osteoblast maturation. Pharmacological CaMKIV inhibition with STO-609 increased bone formation in vitro and enhanced ectopic bone formation in vivo, supporting CaMKIV as a potential anabolic target for bone regeneration.

POTE proteins are known to be expressed in tissues such as normal prostate, placenta, ovary, testis, and embryo, and are collectively referred to as POTE-family proteins based on this organ-specific expression. The POTE gene spans 32 kb on chromosome 21q11.2, although its homologous genes are distributed across eight different chromosomes. POTEE, as a member of the POTE family, has been identified as a Cancer Germline Antigen (CGA) across several cancer types including Colorectal, Pancreatic, Breast, Liver, and Lung cancers. This study aims to elucidate the role of POTE-Paralogs (POTEE & POTEF) as CGA markers in Cervical Cancer (CaCx). Over 90% of CaCx cases are associated with persistent infection by high-risk HPV (HR-HPV); the E6 and E7 oncoproteins of HPV contribute to carcinogenesis through the degradation or inactivation of tumor suppressor proteins p53 and pRB, leading to uncontrolled cell proliferation. Consequently, HPV-positive cervical cancer cell lines HeLa and CaSki lack detectable expression of p53, and the expression of POTE-Paralogs is also markedly decreased, while the HPV-negative CaCx cell line C-33A exhibits high p53 expression correlated with marked upregulation of POTE-Paralogs. Treatment of C-33A cells with a p53-specific inhibitor reduced POTE-Paralogs expression. Conversely, restoring p53 expression in CaSki cells with the chemotherapeutic agent Doxorubicin resulted in increased expression of POTE-Paralogs. Furthermore, silencing of E6/E7 in CaSki cells led to restoration of both p53 and pRB expression, as well as an increase in POTEE & POTEF levels.

Osteoclast-mediated bone resorption is closely linked to bone formation, and any disruption in this process can lead to diseases such as osteoporosis. Matrix metalloproteinase-9 (MMP-9) is a nuclear histone protease that specifically cleaves the N-terminal tail (NT) of histone H3 at osteoclastogenic gene loci, thereby facilitating transcription and osteoclast differentiation. In this study, we developed tandem H3 tail peptides (residues 1-40) fused to a cell-penetrating peptide (CPP) to serve as competitive inhibitors of MMP-9. Both wild-type (WT) and P16G mutant peptides effectively localized to the nucleus, inhibited RANKL-induced osteoclast differentiation, and downregulated MMP-9 target genes (Xpr1, Nfatc1) as well as osteoclast-specific genes (Ctsk, Mmp9, Trap, Oscar) without impacting precursor proliferation. Mechanistically, both peptides inhibited MMP-9-mediated H3 NT clipping and decreased H3K18 acetylation by competitively binding to p300, thus disrupting a crucial epigenetic step necessary for histone clipping. While WT and P16G peptides exhibited similar binding affinities to MMP-9, the P16G mutant was resistant to proteolytic cleavage, allowing it to remain associated with MMP-9 for a longer period, which resulted in more effective inhibition of H3 NT clipping and osteoclastogenesis. Collectively, these findings indicate that histone H3 tail-derived peptides inhibit osteoclast differentiation by simultaneously targeting p300-dependent histone acetylation and MMP-9-mediated histone proteolysis. Our study provides valuable mechanistic insights into the epigenetic regulation of osteoclastogenesis and emphasizes engineered histone-derived peptides as a promising class of selective therapeutic inhibitors for osteoclast-driven bone diseases.

Aging contributes to hepatic steatosis by increasing de novo lipogenesis. The Forkhead box O6 (FOXO6) transcription factor links insulin signaling to lipid metabolism. Activated FOXO6 induces hyperlipidemia and decreases peroxisome proliferator-activated receptor alpha (PPARα), thereby promoting hepatic lipogenesis. In this paper, we describe the role of FOXO6 in hepatic steatosis in aged male rats and liver cells, and examine the relationship between FOXO6 and PPARα, and the functional consequences of their altered interaction. We find that FOXO6 induces lipid accumulation by inhibiting PPARα in aged male rat livers. Our data show that AKT signaling negatively regulates FOXO6-induced hepatic lipid accumulation, and that a key β-oxidation gene, PPARα, is decreased in aged livers. We further demonstrate that FOXO6 activation decreases PPARα expression and increases lipid accumulation. Furthermore, interaction between FOXO6 and PPARα promotes hepatic steatosis in aged males. Also, high glucose upregulates Foxo6, reduces β-oxidation gene expression, and increases cellular TG-mediated lipid accumulation. Transcriptional activation of FOXO6 by aging and high glucose cause lipid accumulation by downregulating PPARα and hyperglycemia-responsive genes in aged male rats and liver cell cultures. We provide evidence that age-related insulin resistance suppresses β-oxidation through interaction between FOXO6 and PPARα, thereby promoting hepatic lipid accumulation in aged male rats.

Metallothioneins (MTs) are metal-binding proteins that are involved in heavy metal homeostasis and protection against oxidative stress. The MT1 family comprises several isoforms that are implicated in various diseases, including cancer. Although the dysregulated expression of MT1 isoforms has been observed in lung cancer, the specific role of MT isoform MT1B remains unclear. To investigate the role of MT1B in lung cancer progression, A549 lung cancer cells were transfected with an MT1B expression vector. In vitro assays were performed to assess cell viability, migration, invasion, and colony formation. Western blot analysis revealed increased expression of epithelial-mesenchymal transition (EMT) markers Snail, vimentin, and N-cadherin, and decreased levels of E-cadherin, indicating EMT induction. In the xenograft model, the MT1B-transfected group formed tumors more rapidly and exhibited significantly increased tumor growth compared to the controls. In addition, RNA sequencing was performed to identify MT1B-dependent gene alterations, and Ingenuity Pathway Analysis (IPA) was applied to characterize the canonical pathways and predicted biological functions associated with these MT1B-specific genes. These findings suggest that cellular MT1B overexpression has the potential to promote lung cancer growth.

Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics - with an increased propensity to form SGs while displaying reduced efficiency in their clearance - resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging.

Modern genomic sequencing techniques have advanced rapidly, thereby improving data production rates and dimensionality. With this accelerated growth, machine learning, especially deep learning, has been leveraged to analyze complex data and complement conventional bioinformatics methods. Deep learning approaches have been successfully applied in genomics, leading to the development of state-of-the-art models and significantly improved interpretation of genomic data. Here, we review deep learning models in four genomic domains: variant calling, gene expression regulation, motif finding, and 3D chromatin interactions. We summarize the key aspects of model development, such as training and generalization, that enable the efficient application of deep learning models in genomic research. Real-world applications have demonstrated the reliability and efficiency of these models for predicting genomic profiles. Finally, we highlight the future directions of deep learning approaches in genomics by discussing the challenges related to genome tokenization and multi-omics data integration. [BMB Reports 2026; 59(1): 60-68].

Aging proceeds in a nonuniform spatiotemporal manner across tissues. While metabolic stress and chronic inflammation are implicated, the underlying mechanisms remain elusive. Here, we propose that imperfect wound healing-a failure of full resolution-creates and sustains pathological niches that drive progressive age-related dysfunction. Using the liver as a model system, we deconstruct this 'imperfect repair'. We posit that it is driven by a pro-fibrotic, non-resolving microenvironment sustained by complex crosstalk between functionally heterogeneous senescent cells and non-senescent scar-associated cell (SAC) populations (including macrophages, endothelial cells (ECs), and hepatic stellate cells (HSCs)). This pathological ecosystem is further shaped by the spatial context of hepatic zonation collapse, and the dysregulation of core signaling hubs, like WNT, Transforming Growth Factor (TGF)-β, and YAP and TAZ (YAP/TAZ). Viewing aging through the lens of imperfect repair provides a unifying framework linking senescence, inflammation, and fibrosis. This perspective shifts the therapeutic paradigm from targeting single senescent cells toward engineering the pathological niche itself, and redirects focus from end-stage disease, to the sub-clinical, spatial origins of tissue vulnerability. [BMB Reports 2026; 59(1): 13-26].