BMB Reports最新文献

Cellular senescence is an irreversible program of cell-cycle arrest that accumulates with age, contributing to chronic inflammation and various age-related diseases. A key feature of senescence paradigms is mitochondrial dysfunction, which involves not just a single defect but a series of coordinated changes in bioenergetics, redox homeostasis, mitochondrial quality control, and organelle interaction. Senescent cells often display a "quantity-quality imbalance" in their mitochondria: while the mitochondrial mass may increase, their efficiency in oxidative phosphorylation decreases, leading to a destabilized membrane potential (ΔΨm) and elevated levels of mitochondrial reactive oxygen species (mtROS). These interrelated changes can exacerbate senescence through persistent stress signaling, impaired turnover of damaged mitochondrial components, and alterations in organelle contacts, such as those between endoplasmic reticulum (ER) and mitochondria, and between mitochondria and lysosomes. Given that these phenotypes differ depending on cell type, triggering factors, and timing, no single assay can adequately define senescence-associated mitochondrial dysfunction. In this review, we present practical, complementary strategies that include extracellular flux-based respiration profiling, ATP output measurement, ΔΨm and ROS assessments, flux-based mitophagy reporters, quantitative network imaging, and contact-site assays. We propose minimal assay bundles that allow for a thorough multidimensional analysis. By establishing standardized, orthogonal measures of mitochondrial quantity and quality, we aim to enhance mechanistic understanding and facilitate the rational evaluation of mitochondria-targeted senolytic and senomorphic therapies.

In this study, we report a novel function of protein phosphatase 1 regulatory subunit 3C (PPP1R3C)-which is known to promote glycogenesis by activating glycogen synthase and to inhibit glycogen breakdown by suppressing glycogen phosphorylase- as a tumor suppressor in endometrial cancer. First, the expression of PPP1R3C was strongly down-regulated in uterine corpus endometrial cancer (UCEC) tissues, and ectopic expression of PPP1R3C led to cell cycle arrest and apoptosis in HEC1A and HEC1B cells derived from UCEC. PPP1R3C also inhibited the growth of xenograft tumors in BALB/c nude mice. We found evidence indicating that the activation of glycogen synthesis was at least partly responsible for the tumor suppressor activity of PPP1R3C. Specifically, inhibition of glycogen synthase abrogated the effect of ectopic PPP1R3C expression on the growth inhibition of UCEC cells. Collectively, our data indicate that PPP1R3C is a tumor suppressor gene functioning through the induction of glycogen synthesis.

Chromatin profiling methods such as ChIP-seq, CUT&RUN, and CUT&Tag differ substantially in background structure, signal distribution, and resolution, complicating direct quantitative comparison across platforms. In this study, we systematically compared conventional and double-crosslink ChIP-seq, CUT&RUN, and CUT&Tag by profiling the Polycomb-associated histone modification H3K27me3 in human cardiomyocytes and the PRC2 catalytic subunit EZH2 in pluripotent stem cells. To enable cross-assay comparison, we developed a biologically informed normalization strategy based on stable Polycomb reference loci, allowing harmonization of signal scales while preserving assay-intrinsic signal architecture. This approach revealed CUT&RUN to preferentially capture broad H3K27me3 domains, whereas CUT&Tag provides sharper and more localized enrichment for both H3K27me3 and EZH2. Together, our results establish a practical framework for cross-platform epigenomic comparison and guide the selection of chromatin profiling strategies.

Solute carrier (SLC) transporters are membrane proteins that facilitate the movement of various substrates, such as nutrients and organic or inorganic ions, across cellular membranes. Recent studies underscore the critical roles of SLC transporters in regulating cancer metabolism, immune evasion, and the tumor microenvironment. Increasing evidence suggests that the SLC39 and SLC30 families of zinc transporters, responsible for importing and exporting zinc into and out of the cytoplasm, respectively, modulate intracellular zinc distribution and signaling and may play a role in cancer initiation or progression. In this review, we discuss the functional roles of these zinc transporters in different cancer types and examine potential mechanisms linking zinc metabolism with oncogenic pathways that contribute to malignancy.

Reactive Oxygen Species (ROS) accumulation disrupts cellular homeostasis, leading to lipid peroxidation, mitochondrial dysfunction, DNA damage, and apoptosis. Sestrin2 (Sesn2) is a critical antioxidant protein that regulates intracellular oxidative stress and protects cells from oxidative damage and apoptosis. However, the role of Sesn2 in ovarian reproductive function remains unclear. In this study, we examined Sesn2 expression in response to oxidative stress using granulosa-like KGN cells derived from human ovarian granulosa cell tumors, mouse granulosa cells, and an oxidative stress mouse model. Additionally, we investigated the protective Sesn2 functions and its mechanisms of action in promoting granulosa cell survival. The results showed that Sesn2 expression markedly increased in granulosa cells exposed to hydrogen peroxide (H2O2) and in oxidative stress models induced by 3-nitropropionic acid (3-NP). Oxidative stress in ovarian granulosa cells increases ROS levels, decreases cell viability, and triggers apoptosis. Sesn2 silencing further aggravates granulosa cell damage, whereas targeting Sesn2 under oxidative stress conditions reduces ROS levels and modulates apoptosis through the p53/Caspase-3 signaling pathway. These findings highlight the pivotal role of Sesn2 in protecting cells against ROS-induced damage, preserving follicular health, and supporting ovarian function and reproductive capacity.

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.

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.