Search Results (903)

Aurora kinase B (AURKB), a serine/threonine protein kinase, is essential for accurate chromosome segregation and cytokinesis during mitosis. Dysregulation of AURKB, often characterized by its overexpression, has been implicated in various malignancies, including breast cancer. However, the mechanisms governing its dysregulation remain incompletely understood. Here, we identify a pivotal role for the MOF/MSL complex—which includes the histone acetyltransferase MOF (KAT8)—in modulating AURKB stability through acetylation at lysine 215 (K215). This post-translational modification inhibits AURKB ubiquitination, thereby stabilizing its protein levels. MOF/MSL-mediated AURKB stabilization promotes the proper assembly of the chromosomal passenger complex (CPC), ensuring mitotic fidelity. Notably, inhibition of MOF reduces AURKB K215 acetylation, leading to decreased AURKB expression and activity. Consequently, this downregulation suppresses expression of the downstream oncogene c-MYC, ultimately attenuating the malignant proliferation of breast cancer cells. Collectively, our findings reveal a novel mechanism by which lysine acetylation regulates AURKB stability, highlight the significance of the MOF-AURKB-c-MYC axis in breast cancer progression, and suggest potential therapeutic strategies targeting this pathway in clinical settings. Full article

Background: Casein kinase I-like (CKL) protein is a member of the serine/threonine kinase CKI family and plays a pivotal regulatory role in various eukaryotic cellular processes, including stress responses. Objectives: This study aims to systematically identify the CKL gene family in the tomato genome and investigate its responsiveness to abiotic stress. Methods: Members of SlCKL were identified through genome-wide bioinformatics analysis, and their physicochemical properties, chromosomal localization, gene structure, conserved domains, phylogenetic relationships, cis-acting elements, cross-species collinearity, and tissue expression profiles were comprehensively analyzed. The expression patterns of SlCKL genes under abiotic stress were validated using real-time quantitative PCR. Results: A total of 16 SlCKL genes were identified and classified into three subfamilies (I–III), which are unevenly distributed across nine chromosomes, predominantly clustered at the ends. The gene structure, motifs, and functional domains exhibit high conservation. Collinearity analysis revealed stronger synteny between tomato and Arabidopsis thaliana or pepper compared to rice, maize, or tobacco, suggesting a common ancestral origin. The tissue expression profile indicates that SlCKLs are preferentially transcribed in roots. Promoter analysis and qRT-PCR validation demonstrated differential responses of SlCKLs to various abiotic stresses, such as drought, salt, heat, cold, and ABA treatment. Conclusions: This study represents the first systematic identification of the tomato SlCKL gene family, elucidating its evolutionary relationships, structural characteristics, tissue-specific expression patterns, and differential responsiveness to abiotic stress, thereby providing a critical foundation for further investigation into the molecular mechanisms underlying CKL-mediated abiotic stress adaptation in tomatoes. Full article

Protein kinases and phosphatases are essential for post-translational regulation, enabling bacteria to adapt to environmental stresses and modulate virulence. While prior reviews have broadly covered their roles in stress response, antibiotic resistance, and virulence, this article updates specifically on the roles of histidine kinases (HKs) and serine/threonine kinases (STKs) in mediating phage-bacteria interactions. A key aspect is phage-encoded kinases, which hijack bacterial signalling by phosphorylating and disrupting host processes to promote infection. Despite their importance, significant gaps remain in understanding these regulatory networks. This microreview highlights both the unresolved mechanisms and the therapeutic potential of targeting kinase pathways—for instance, by disrupting phage evasion strategies or enhancing phage-based antimicrobial therapies. Full article

Casein Kinase II (CK2) is a ubiquitously present serine/threonine kinase essential for mammalian development. CK2 holoenzyme is a tetramer with two highly related catalytic subunits (α or α’) and two regulatory ß subunits. Global deletion of the α or β subunit in mice is embryonically lethal. We and others have shown that CK2 is overexpressed in leukemia cells and plays an important role in cell cycle, survival, and resistance to the apoptosis of leukemia stem cells (LSCs). To study the role of CK2α in adult mouse hematopoiesis, we generated hematopoietic cell-specific CK2α-conditional knockout mice (Vav-iCreCK2 ^f/f). Here we report the generation and validation of a novel mouse model that lacks CK2α in the hematopoietic compartment. Vav-iCreCK2α ^f/f mice were viable without dysmorphic features and showed a mild phenotype under baseline conditions. In Vav-iCreCK2α ^f/f mice, the blood count showed a significant decrease in total red blood cells and platelets. The spleen was enlarged in Vav-iCreCK2α ^f/f mice with evidence of extramedullary hematopoiesis. HSC and early progenitor cell compartments showed expansion in CK2α-null bone marrow, suggesting that the absence of CK2α impaired their proliferation and differentiation. Given the established roles of CK2 in cell cycle regulation and the findings reported here, further functional studies are warranted to investigate the role of CK2α in HSC self-renewal and differentiation. This mouse model serves as a valuable tool for understanding the role of CK2α in normal and malignant hematopoiesis. Full article

Phase-separated membraneless biomolecular condensates in the cytoplasm and nucleus are now recognized to play a major role in modulating diverse functions in mammalian cells, and contribute to cancer pathogenesis through dysregulated function of condensates of transcription factors such as STAT3 and fusion oncoproteins. Oral cancer, the sixth most prevalent malignancy worldwide, in the absence of overt causes such as tobacco or alcohol, most frequently occurs in a U-shaped zone (floor of mouth, side of tongue, anterior fauces and retromolar region) reflecting the path of liquid transit through the mouth. The cellular basis for this “high-risk” zone and the biochemical mechanisms used by oral cells to combat repetitive tonicity and temperature stresses are incompletely understood. We had previously observed that at 37 °C, in OECM1 oral carcinoma cells, cytoplasmic condensates of antiviral human GFP-MxA GTPase disassembled within 1–2 min of exposure of cells to saliva-like one-third hypotonicity, and underwent “spontaneous” reassembly in the next 5–7 min. Moreover, hypotonic beverages (water, tea, coffee), investigated at 37 °C, triggered this condensate cycling. In the present studies we investigated whether this process was temperature sensitive, representative of cold vs. warm drinks. We observed a slowing of this cycle at 5 °C, and speeding up at 50 °C. The involvement in this disassembly/reassembly process of WNK-SPAK/OSR1 serine-threonine kinase pathway, best studied for regulation of water and Na, K and Cl influx and efflux in kidney tubule cells, was evaluated by us in oral cells using pathway inhibitors WNK463, WNK-IN-11 and closantel. The pan-WNK inhibitor WNK463 inhibited hypotonicity-driven condensate disassembly, while the SPAK/OSR1 inhibitor closantel markedly slowed reassembly. Unexpectedly, the WNK1-selective inhibitor (WNK-IN-11), triggered a dramatic and rapid (within 1 h) spheroid to fibril transition of GFP-MxA condensates in live cells, but without affecting MxA antiviral function. The new data suggest a novel hypothesis for the anatomic localization of oral cancer in the U-shaped “high-risk” zone in the mouth: dysfunction of biomolecular condensates in oral cells along the beverage transit pathway through the mouth due to repetitive tonicity and temperature stresses that might underlie a prooncogenic progression. Full article

Background/Objectives: Non-melanoma skin cancer (NMSC) is among the most common cancers in the United States, with solar ultraviolet (UV) radiation being a primary etiological factor. T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase activated by solar UV, has been implicated in skin carcinogenesis. This study aimed to investigate the mechanistic role of TOPK in solar UV-induced skin damage and tumor development. Methods: RNA sequencing (RNA-seq) was performed on skin tissues from wild-type (WT) and TOPK knockout (KO) mice, with or without solar UV exposure, to identify TOPK-regulated genes and pathways. Follow-up experiments using Western blotting, immunofluorescence, and luciferase assays were conducted in vitro and in vivo. Functional assays included 3D spheroid and Transwell co-culture systems involving cutaneous squamous cell carcinoma (cSCC) and fibroblast cells. Results: TOPK deletion altered gene expression profiles and inhibited solar UV-induced activation of multiple signaling pathways, including cytokine–cytokine receptor interaction, PI3K/AKT, MAPKs, PKG, cAMP, and calcium signaling. RNA-seq and protein analyses identified interleukin-19 (IL19) as a key downstream effector suppressed by TOPK deletion. In cSCC and fibroblast cells, TOPK knockdown reduced IL19 expression and secretion. IL19 promoted cSCC growth and activated PI3K/AKT, ERK, and TOPK pathways. Additionally, chronic TGFβ exposure increased IL19 expression and activated fibroblasts, as indicated by elevated αSMA and FAPα levels. Conclusions: These findings establish TOPK as a central regulator of solar UV-induced skin carcinogenesis, partially via modulation of IL19 signaling and fibroblast activation. Targeting TOPK may offer a novel strategy for the prevention and treatment of NMSC. Full article

Medical research is at the forefront of addressing pressing global challenges, including preventing and treating cardiovascular, autoimmune, and oncological diseases, neurodegenerative disorders, and the growing resistance of pathogens to antibiotics. Understanding the molecular mechanisms underlying these diseases, using advanced medical approaches and cutting-edge technologies, structure-based drug design, and personalized medicine, is critical for developing effective therapies, specifically anticancer treatments. Background/Objectives: One of the key drivers of cancer at the cellular level is the abnormal activity of protein enzymes, specifically serine, threonine, or tyrosine residues, through a process known as phosphorylation. While tyrosine kinase-mediated phosphorylation constitutes a minor fraction of total cellular phosphorylation, its dysregulation is critically linked to carcinogenesis and tumor progression. Methods: Small-molecule inhibitors, such as imatinib or erlotinib, are designed to halt this process, restoring cellular equilibrium and offering targeted therapeutic approaches. However, challenges persist, including frequent drug resistance and severe side effects associated with these therapies. Nanomedicine offers a transformative potential to overcome these limitations. Results: By leveraging the unique properties of nanomaterials, it is possible to achieve precise drug delivery, enhance accumulation at target sites, and improve therapeutic efficacy. Examples include nanoparticle-based delivery systems for TKIs and the combination of nanomaterials with photothermal or photodynamic therapies to enhance treatment effectiveness. Combining nanomedicine with traditional treatments holds promise and perspective for synergistic and more effective cancer management. Conclusions: This review delves into recent advances in understanding tyrosine kinase activity, the mechanisms of their inhibition, and the innovative integration of nanomedicine to revolutionize cancer treatment strategies. Full article

Wheat (Triticum aestivum L.), a staple crop of global significance, faces constant biotic stress threats, with powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt) being particularly damaging. In this study, a multi-year single-site experiment was conducted to minimize the environmental impacts, and a five-level classification system was used to assess powdery mildew resistance. A 660K SNP array genotyped 204 wheat germplasms, followed by GWAS. SNP loci with a −log₁₀(p) > 3.0 were screened and validated across repeats to identify those associated with powdery mildew (Pm) resistance. Twelve SNPs were consistently associated with Pm resistance across multiple years. Of these, three colocalized with previously reported Pm-resistance gene or QTL regions, and the remaining nine represented potentially novel loci. The candidate genes identified included leucine-rich repeat (LRR) and NB-ARC immune receptors, as well as pathogen-related, thioredoxin, and serine threonine-protein kinase genes. Overall, the SNP loci and candidate genes identified in this study provide a basis for further fine mapping and cloning of the genes involved in relation to Pm resistance. Full article

Background/Objectives: Death-associated protein kinase 1 (DAPK1) is a serine/threonine kinase that plays a crucial role in cancer by regulating apoptosis through interactions with TP53. Aberrant expression of DAPK1 was shown in certain types of human cancer contributing to tumor progression and chemoresistance. This study aimed to investigate the role of DAPK1 in high-grade serous ovarian cancer (HGSOC) and to evaluate the therapeutic potential of restoring its kinase activity, including the use of truncated DAPK1 variants, to overcome chemoresistance and enhance tumor suppression. Methods: Gene expression analysis was performed on ovarian cancer tissues compared to benign controls to assess DAPK1 downregulation and its epigenetic regulation. Prognostic relevance was evaluated in a cohort of 1436 HGSOC patient samples. Functional restoration of DAPK1 was conducted in HGSOC cell lines and patient-derived primary tumor cells using vector-based expression or in vitro-transcribed (IVT) DAPK1 mRNA, including the application of truncated DAPK1 (ΔDAPK1) forms. To assess apoptosis, Caspase activation assays, 2D-colony formation assays, and cell survival assays were performed. To analyze the reactivation of DAPK1 downstream signaling, phosphorylation of p53 at Ser20 and the expression of p53 target proteins were examined. Chemosensitivity to Paclitaxel and Cisplatin was quantified by changes in IC₅₀ values. Results: DAPK1 expression was significantly downregulated in ovarian cancer compared to benign tissue, correlating with epigenetic silencing, and showed prognostic value in early-stage HGSOC. Restoration of DAPK1 activity, including ΔDAPK1 variants, led to phosphorylation of p53 Ser20, increased expression of p53 target proteins, and Caspase-dependent apoptosis. Reactivation of DAPK1 sensitized both established HGSOC cell lines and patient-derived ascites cells to Paclitaxel and Cisplatin. These effects occurred through both p53-dependent and p53-independent pathways, enabling robust tumor suppression even in p53-mutant contexts. Conclusions: Reactivation of DAPK1, particularly through truncated variants, represents a promising therapeutic strategy to overcome chemoresistance in HGSOC. The dual mechanisms of tumor suppression provide a strong rationale for developing DAPK1-based therapies to enhance the efficacy of standard chemotherapy, especially in patients with chemoresistant or p53-deficient tumors. Future work should focus on optimizing delivery approaches for DAPK1 variants and assessing their synergistic potential with emerging targeted treatments in clinical settings. Full article

STRAP (serine-threonine kinase receptor-associated protein), a WD domain-containing 38.5 kDa protein, was first identified in TGF-ß signaling and participates in scaffold formation in numerous cellular multiprotein complexes. It is involved in the regulation of several oncogenic biological processes, including cell proliferation, apoptosis, migration/invasion, tumor initiation and progression, and metastasis. STRAP upregulation in epithelial tumors regulates several signaling pathways, such as TGF-ß, MEK/ERK, Wnt/β-Catenin, Notch, PI3K, NF-κB, and ASK-1 in human cancers, including colon, breast, lung, osteosarcoma, and neuroblastoma. The upregulation of STRAP expression is correlated with worse survival in colorectal cancer following post-adjuvant therapy. Strap knockout sensitizes colon tumors to chemotherapy, delays APC-induced tumor progression, and reduces cancer cell stemness. The loss of Strap disrupts lineage differentiation, delays neural tube closure, and alters exon skipping, resulting in early embryonic lethality in mice. Collectively, the purpose of this review is to update and describe the diversity of targets functionally interacting with STRAP and to rationalize the involvement of STRAP in a variety of signaling pathways and biological processes. Therefore, these in vitro and in vivo studies provide a proof of concept that lowering STRAP expression in solid tumors decreases tumorigenicity and metastasis, and targeting STRAP provides strong translational potential to develop pre-therapeutic leads. Full article

The term autophagy identifies several mechanisms that mediate the degradation of intracellular and extracellular components via the lysosomal pathway. Three main forms of autophagy exist, namely macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy, which have distinct mechanisms but share lysosomes as the final destination of their cargo. A basal autophagic flux is crucial for the maintenance of cellular homeostasis, being involved in the physiological turnover of proteins and organelles. Several stressors, including nutrient shortage and genotoxic and oxidative stress, increase the autophagic rate, which prevents the accumulation of damaged and potentially harmful cell components, thus preserving cell viability. In this context, several studies have highlighted the role of MAPKs, serine–threonine kinases activated by several stimuli, in linking oxidative stress and autophagy. Indeed, several oxidative stressors activate autophagy by converging on MAPKs, directly or indirectly. In this regard, the different transcription factors that bridge MAPKs and autophagic activation are here described. In this review, we summarize the current knowledge regarding the regulation of autophagy by MAPK, including the atypical ones, with a particular focus on the regulation of autophagy by oxidative stress. Full article

Ataxia-telangiectasia is a rare autosomal recessive disorder that is difficult to diagnose due to its unpredictable presentation. It is characterized by cerebellar degeneration, telangiectasias, immunodeficiency, frequent pulmonary infections, and tumors. Immune system abnormalities manifest as disruptions in both cellular and humoral immunity. The most common findings include decreased levels of immunoglobulin classes (IgA, IgM, IgG, and IgG subclasses) and a reduced number of T and B lymphocytes. A four-year-old girl was initially evaluated and treated for skin lesions that presented as crusts spreading across her body. She was monitored by a pulmonologist due to frequent bronchial obstructions. Over time, she developed bilateral scleral telangiectasia, saccadic eye movements, and impaired convergence. Her gait was wide-based and unstable, with truncal ataxia and a positive Romberg sign. Laboratory tests revealed decreased immunoglobulin G levels, subclass IgG4 levels, elevated alpha-fetoprotein, and a reduced number of T and B lymphocytes. Brain magnetic resonance imaging showed cerebellar atrophy. Whole-exome sequencing identified heterozygous variants c.1564-165del, p.(Glu5221lefsTer43), and c.7630-2A>C in the serine/threonine-protein kinase ATM (ataxia-telangiectasia mutated) gene, confirming the diagnosis of ataxia-telangiectasia. Following diagnosis, treatment with intravenous immunoglobulin replacement was initiated along with infection prevention and management. The goal of this case report is to raise awareness of the atypical initial presentation that may lead to a diagnostic delay. We emphasize the importance of considering ataxia-telangiectasia in the differential diagnosis, even when classical neurological signs are not yet evident. Full article

Butein (3,4,2′,4′-tetrahydroxycalone) is a chalcone derivative and plant polyphenol extracted from Rhus verniciflua Stokes. Butein has an open C-ring structure and a variety of biological activities. Molecular mechanisms by which butein could affect cell viability, ROS levels, mitochondrial function, apoptosis, and necrosis in prostate cancer cells were investigated using 2D monolayer and 3D sphere culture systems. Cytotoxicity and cell cycle monitoring showed that butein treatment decreased cell viability and increased peaks of sub-G₀/G₁ and G₂/M phases analyzed by flow cytometry. These changes were observed with a concurrent induction of DNA damage, apoptosis, and necrosis. Although 3D spheres treated with butein showed decreased cell viability, they were slightly more resistant than cells in 2D cultures. This phenomenon was accompanied by an increase in mediators of apoptosis and necrosis. Monitoring changes of apoptosis-related proteins via Western blot showed that butein decreased caspase-3, PARP, and Bcl-2, but increased Bax. Meanwhile, butein increased levels of p-receptor interacting serine/threonine–protein kinase 3 (p-RIP3) and p-mixed lineage kinase domain-like kinase (p-MLKL) known to be mediators of necrosis. Overall, our data suggest that butein can induce apoptosis and necrosis of prostate cancer cells by regulating pro- and anti-apoptotic proteins via ROS. Thus, butein might be a potential agent for treating prostate cancer. Full article

Although the global incidence of tuberculosis has declined in recent years, tuberculosis remains a major global public health challenge. The Mycobacterium tuberculosis complex (MTBC) including M. tuberculosis, M. bovis, M. microti, etc., is the deadliest Mycobacterium spp. that needs more attention. Research on M. microti is significant as it is a zoonotic pathogen that can spread between animals and humans. By exploring the function of a transglutaminase in M. microti (MmTG), which is widely distributed in Mycobacterium and other species, a potential cytotoxic effector has been characterized. MmTG inhibits cell proliferation by inducing the phosphorylation of RIPK1 (receptor-interacting serine/threonine-protein kinase 1) and the Cys159 of MmTG is the highly conserved residue related to its cytotoxicity. Understanding MmTG and its homologs can provide more insights into the pathogenic mechanisms of mycobacteria and contribute to the development of more effective therapeutic strategies against mycobacterial infections. Full article

Background/Objectives: Desiccation profoundly influences the distribution and abundance of intertidal seaweeds, necessitating robust molecular adaptations. Sargassum muticum is a brown seaweed inhabiting intertidal rocky substrates. During low tides, this species undergoes periodic aerial exposure. Such environmental conditions necessitate robust physiological mechanisms to mitigate desiccation stress. Yet, the molecular basis of this adaptation remains poorly understood. Methods: To investigate desiccation-responsive genes and elucidate the underlying mechanisms of adaptation, we exposed S. muticum to 6 h of controlled desiccation stress in sterilized ceramic trays, simulating natural tidal conditions, and performed comparative transcriptome analysis using RNA-seq on the Illumina NovaSeq 6000 platform. Results: High-quality sequencing identified 66,192 unigenes, with 1990 differentially expressed genes (1399 upregulated and 591 downregulated). These differentially expressed genes (DEGs) were categorized into regulatory genes—including mitogen-activated protein kinase (MAPK), calmodulin, elongation factor, and serine/threonine-protein kinase—and functional genes, such as heat shock protein family members (HSP20, HSP40, and HSP70), tubulin (TUBA and TUBB), and endoplasmic reticulum homeostasis-related genes (protein disulfide-isomerase A6, calreticulin, and calnexin). Gene Ontology (GO) enrichment highlighted upregulated DEGs in metabolic processes like glutathione metabolism, critical for oxidative stress mitigation, while downregulated genes were linked to transport functions, such as ammonium transport, suggesting reduced nutrient uptake during dehydration. KEGG pathway analysis revealed significant enrichment in “protein processing in endoplasmic reticulum” and “MAPK signaling pathway-plant”, implicating endoplasmic reticulum stress response and conserved signaling cascades in desiccation adaptation. Validation via qRT-PCR confirmed consistent expression trends for key genes, reinforcing the reliability of transcriptomic data. Conclusions: These findings suggest that S. muticum undergoes extensive biological adjustments to mitigate desiccation stress, highlighting candidate pathways for future investigations into recovery and tolerance mechanisms. Full article