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ACTH stimulates the incorporation of 14C-leucine into proteins of adrenal tumor cells in culture. This stimulation though about 20% over controls is statistically significant. Cyclic AMP did not reproduce the stimulation observed with ACTH.
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This study aims to investigate the toxicity of di(2-ethylhexyl) phthalate (DEHP) and the potential molecular mechanisms of DEHP-induced bladder cancer (BLCA) using network toxicology and molecular docking strategies. The toxicity of DEHP was assessed using Prox-II software, and potential targets for DEHP-induced BLCA were identified by integrating data from ChEMBL database, Search Tool for Interactions of Chemicals, SwissTargetPrediction, GeneCards, Therapeutic Target Database, Online Mendelian Inheritance in Man, and The Cancer Genome Atlas. STRING database and Cytoscape were employed to construct target networks and determine core targets. The expression levels of core targets were analyzed using R. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on potential and core targets. Molecular docking was carried out using CB-Dock 2 to verify the interactions between DEHP and core targets. A total of 105 potential targets related to DEHP-induced BLCA were identified, from which 7 core targets were selected: cyclin-dependent kinase 1, interleukin 6, cyclin-dependent kinase 2, cyclin B1, Erb-B2 receptor tyrosine kinase 2, cyclin B2, and B-cell lymphoma 2. IL-6 and B-cell lymphoma 2 showed downregulated expression in tumor tissues, while cyclin-dependent kinase 1, cyclin-dependent kinase 2, cyclin B1, Erb-B2 receptor tyrosine kinase 2, and cyclin B2 were upregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these targets were enriched in cell signaling and cancer-related pathways. Molecular docking confirmed that DEHP interacts with these core targets. DEHP may promote the development of BLCA by interacting with key proteins and signaling pathways. This study provides a theoretical basis for understanding the molecular mechanisms of DEHP-induced BLCA and offers references for future prevention and treatment strategies.
The high mobility group As (HMGAs) belong to a family of nonhistone nuclear proteins that orchestrate the assembly of nucleoprotein complexes. Through a complex network of protein-DNA and protein-protein interaction, they play important roles in gene transcription, recombination, and chromatin structure. This protein family is involved, through different mechanisms, in both benign and malignant neoplasias. We have recently reported that transgenic mice carrying the Hmga1 or Hmga2 genes under transcriptional control of the cytomegalovirus promoter develop pituitary adenomas secreting prolactin and growth hormone. We have shown that the mechanism of the HMGA2-induced pituitary adenoma is based on the increased E2F1 activity. The expression profile of mouse normal pituitary glands and adenomas induced in HMGA transgenic mice revealed an increased expression of the ccnb2 gene, coding for the cyclin B2 protein, in the neoplastic tissues compared with the normal pituitary gland. Here, we show, by electrophoretic mobility shift assay and chromatin immunoprecipitation, a direct binding of HMGA proteins to the promoter of ccnb2 gene, whereas luciferase assays showed that HMGAs are able to up-regulate ccnb2 promoter activity. Finally, we report an increased CCNB2 expression in human pituitary adenomas of different histotypes that is directly correlated with HMGA1 and HMGA2 expression. Because cyclin B2 is involved in the regulation of the cell cycle, these results taken together indicate that HMGA-induced cyclin B2 overexpression gives an important contribution to experimental and human pituitary tumorigenesis.
The JAGGED transcription factor family regulates lateral organ development across angiosperms. In soybean (Glycine max Merr.), a D9H mutation in the EAR repression motif of GmJAG1 causes a narrow-leaflet phenotype and explains over 70% of phenotypic variance in leaf shape. Because this mutation does not affect the zinc finger DNA-binding domain, both alleles bind identical targets but differ in repressor recruitment. Previous studies mapped GmJAG1 binding sites, but the functional targets controlling leaf morphology are uncharacterized. Here, we used comparative transcriptomics across four soybean genotypes with contrasting leaf shape, spanning a developmental time series from shoot apex to mature leaf, and identified 1567 putative candidate target genes. GmJAG1 expression was confined to the shoot apex, yet 99.1% of candidate targets maintained differential expression throughout development. We found that neither Kip-Related Protein (KRP) cell cycle inhibitors nor Cyclin-Dependent Kinases (CDKs) showed differential expression despite binding evidence in Arabidopsis. However, D-type cyclins were upregulated in narrow-leaf genotypes suggesting that soybean GmJAG1 acts through cyclin-mediated rather than KRP-mediated cell cycle regulation described in Arabidopsis- a divergence in regulatory logic between the two species. Pathway analysis revealed enrichment of auxin (1.8-fold, P = 0.02) and salicylic acid (fourfold, P = 0.016) genes among JAG1D9H targets. Filtering by differential expression, binding data, phenotype correlation, and co-expression network membership identified 79 high-confidence targets, including orthologs of NPH3 (phototropin-mediated leaf flattening), MIK2 (cell wall integrity sensing), RD22 (ABA-responsive stress signaling), and SCL23 (GRAS transcription factor in bundle sheath development). These candidates provide targets for functional validation and breeding in legumes.
Entry of budding yeast cells into the mitotic cell cycle requires the activity of a conserved regulatory kinase encoded by the CDC28 gene. The kinase is thought to trigger entry into the cell cycle or START, through association with a number of regulatory subunits known as G1 cyclins. A number of genes whose transcription is dependent on CDC28 and thus linked to START are controlled by two transcription factors, SWI4 and SWI6. The genes controlled by SWI4 and SWI6 include two known G1 cyclins (CLN1 and CLN2), a putative new G1 cyclin (HCS26), and the HO gene whose product initiates cell type switching. SWI4 and SWI6 act through a repeated sequence element, SCB (SWI4,6-dependent cell cycle box), found 2-10 times in the upstream regulatory sequences of target genes. We have constructed a library of mutants in the SCB using doped oligonucleotide mutagenesis. All single base pair changes examined compromised the ability of the SCB to activate transcription in vivo. Analysis of the behaviour of the mutant SCBs in an in vitro DNA binding assay shows that the inability to activate transcription can be explained by reduced binding of SWI4 and SWI6 to the mutant SCBs. This analysis, together with a consideration of the SCBs found upstream of known SWI4,6-dependent genes, leads to the proposal of a revised consensus sequence for this important regulatory element.
Hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer is the most common biologic subtype and carries a persistent risk of recurrence, particularly in patients with high-risk, early-stage disease. Cyclin-dependent kinase 4 and 6 inhibitors, initially established as a standard component of first-line therapy in the metastatic setting based on improvements in progression-free and overall survival, have since been evaluated in the adjuvant setting. While adjuvant palbociclib did not improve invasive disease-free survival, the monarchE and NATALEE trials demonstrated that abemaciclib and ribociclib, respectively, reduce recurrence risk in patients with high-risk, early-stage disease, with emerging overall survival data further supporting their use. However, the absolute magnitude of benefit varies substantially with baseline risk, and treatment-related toxicity and adherence challenges must be considered, as approximately 20% to 25% of patients discontinue therapy before completion. The integration of these agents into clinical practice also intersects with ongoing efforts to deescalate axillary surgery, as treatment eligibility has been largely defined by anatomic staging, particularly nodal status. Available data suggest that the incremental impact of axillary surgery on identifying candidates for cyclin-dependent kinase 4 and 6 inhibition is modest, especially among the favorable-risk populations now eligible for surgical deescalation. As the field evolves, advances in molecular risk stratification, genomic profiling, and dynamic biomarkers are poised to shift treatment selection from anatomic staging toward biologically driven approaches. Multidisciplinary decision-making that integrates tumor biology, anticipated absolute benefit, toxicity, patient preferences, and surgical considerations will be essential to ensure individualized care.
Precise temporal control of DNA replication initiation is essential for faithful cell division, yet there are conflicting prevailing models for how cells trigger origin firing. Here, we demonstrate that human origins are not fired at fixed thresholds of cell cycle regulators E2F, APC/CCdh1, CDK2/1, and CDC7. Instead, origin firing is triggered at a tunable CDK2/1 threshold that is gated by either CDC7 or APC/CCdh1 activity. CDC7 phosphorylates MCM helicase, enabling Cyclin E-CDK2 to trigger origin firing at low CDK2/1 activity, independent of APC/CCdh1 inactivation. In contrast, APC/CCdh1 inactivation enables Cyclin A-CDK1 to phosphorylate MCM at distinct CDK2/1-specific sites and trigger origin firing, independent of CDC7 activity. Strikingly, this requires much higher CDK2/1 activity, which CDK2 cannot normally reach alone. Thus, having two distinct routes necessitates blocking both routes to prevent S phase: either by inhibiting CDC7 or CDK2 while also preventing APC/CCdh1 inactivation or inhibiting CDK1.
BACKGROUND: Progesterone induces rapid cellular responses in progesterone receptor (PR)-negative ovarian cancer cells that are consistent with non-genomic progesterone signaling. Vasohibin-2 (VASH2), originally identified as a pro-angiogenic factor, has recently been recognized as a tubulin carboxypeptidase involved in microtubule regulation. AIMS: This study investigated the association of progesterone treatment with VASH2-related molecular changes and paclitaxel sensitivity in ovarian cancer cells. METHODS: Two PR-negative ovarian cancer cell lines expressing membrane progesterone receptors (mPRs) were treated with progesterone. VASH2 mRNA expression was evaluated by RT-qPCR, whereas detyrosinated tubulin and cyclin B1 expression were assessed by western blotting. Paclitaxel and gemcitabine sensitivities were determined using WST-1 cell viability assays. RESULTS: Progesterone treatment was associated with increased VASH2 mRNA expression, enhanced tubulin detyrosination, cyclin B1 accumulation, and significantly reduced paclitaxel IC50 values in both cell lines. In contrast, progesterone had no significant effect on gemcitabine sensitivity. CONCLUSION: Progesterone treatment was associated with increased VASH2 expression, enhanced tubulin detyrosination, and increased paclitaxel sensitivity in PR-negative ovarian cancer cells. These findings provide in vitro evidence supporting further mechanistic and preclinical investigation of progesterone as a potential adjunct to paclitaxel therapy.
In order to sustain genomic stability by correct DNA replication and mitosis and thus avoid malignant transformation of cells, the cell cycle is a strictly regulated process. Aberrant cell cycle regulation and defects in mitosis in malignant cells are targets of various cancer therapies. Cancer cells may survive antimitotic treatment due to mitotic slippage with a residual activity of the ubiquitin ligase anaphase-promoting complex (APC/C) and a continuous slow ubiquitin-proteasome-dependent cyclin B-degradation leading to mitotic exit. The combination of antimitotic chemotherapeutics with proteasome inhibitors to block cyclin B-proteolysis or with targeted inhibitors of the APC/C and the antiapoptotic protein Mcl-1 seems a promising approach to improve treatment response in different malignancies by enhancing mitotic arrest and apoptosis.The influence of conventional spindle poisons and new targeted substances and of their combinations on mitosis and apoptosis has not yet been conclusively clarified. Most models have been verified on cell lines whose biology may differ from that of tumors growing in vivo. To study the impact of various antimitotic substances on cell proliferation, especially detect onset of apoptosis depending on different cell cycle phases and thus to identify a possibly entity-dependent mechanism of those agents and their combinations, a combined approach with live-cell imaging and soft-agar colony assays in cultured patient-derived xenografts (PDX) was established.
Eukaryotic cell division is regulated by CDK activity that must reach critical CDK threshold levels to progress through cell cycle stages. In low-mitogen, low-CDK environments, cells exit the cell cycle into a non-proliferative quiescent state, G0, that plays essential roles in stem cell maintenance and cellular homeostasis. CIZ1 regulates cell cycle and epigenetic programmes, and CIZ1 ablation promotes genomic instability after release from quiescence. Here, we show that CIZ1 contributes to mechanisms that temporally regulate cell cycle transitions in post-quiescent cells. CIZ1-/- (CIZ1 KO) fibroblasts re-entering the cell cycle from quiescence have reduced G1 phase and cell cycle length, mediated by increased intracellular CDK activity and early restriction point bypass via G1/S cyclin overexpression. In addition, CIZ1-/- cells are deficient in cyclin A chromatin binding and require increased CDK activity to initiate DNA replication, leading to DNA replication stress. Importantly, ectopic expression of CIZ1 or addition of recombinant CIZ1 reinstates the CDK threshold for initiation of DNA replication, reversing DNA replication stress and increasing replication fork rates. These data suggest that in post-quiescent cells, CIZ1 determines the threshold CDK activity required for the G1/S transition to prevent DNA replication stress.
Li-Ru-Kang (LRK) has been commonly used in the treatment of hyperplasia of mammary gland (HMG) as a cipher prescription and achieved obvious therapeutic effects. However, the bioactive compounds and underlying pharmacological mechanisms remain unclear. This study aims to decipher the bioactive compounds and potential action mechanisms of LRK in the treatment of HMG using an integrated pharmacology approach. The ingredients of LRK and the corresponding drug targets were retrieved through drug target databases and were used to construct the "compound-target-disease" network and function-pathway network. Ultimately, 89 compounds and 2150 drug targets were collected. Gene ontology enrichment analysis revealed that mammary gland alveolus development and mammary gland lobule development were the key biological processes and were regulated simultaneously by three direct targets, including androgen receptor (AR), estrogen receptor (ER) and cyclin-D1. Moreover, 14 compounds of LRK were directly involved in the regulation of the three aforementioned targets. KEGG pathway enrichment analysis found that five signaling pathways and seven direct targets were closely related with HMG treatment by LRK. The results of animal experiments showed that LRK significantly improved the histopathological status of HMG in rats. Additionally, LRK markedly regulated the protein expressions of AR, cyclin-D1, MMP2, MMP3 and MMP9. But interestingly, the effect of LRK on ER was not obvious. This study demonstrated that LRK exerted its therapeutic efficacy based on multi-components, multi-targets and multi-pathways. This research confirms the advantages of network pharmacology analyses and the necessity for experimental verification.
BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, and the prognosis of advanced GC remains poor. Systematic identification of robust biomarkers through multi-cohort integration and computational prioritization may facilitate the discovery of novel therapeutic targets. AIM: To identify key genes associated with gastric cancer progression through integrative multi-omics analysis and to elucidate the biological functions and molecular mechanisms of the top-prioritized candidate gene. METHODS: Comprehensive bioinformatics analyses integrating The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) datasets were performed using differential expression analysis, weighted gene co-expression network analysis (WGCNA), Cox regression, and eight machine-learning algorithms to systematically identify and prioritize GC-associated hub genes. Among the identified candidates, CPVL was selected for further validation based on its diagnostic and prognostic performance. CPVL expression and clinical relevance were validated by independent datasets and immunohistochemistry. Lentiviral constructs were used to overexpress or silence CPVL in GC cell lines. Functional assays were performed, including CCK-8, colony formation, EdU incorporation, and flow cytometry, to assess cell proliferation and cell-cycle distribution. Western blotting and JAK2 inhibitor (AZD1480) rescue experiments were performed to elucidate the underlying mechanisms, and a nude mouse xenograft model was used to evaluate tumorigenicity in vivo. RESULTS: Multi-cohort screening identified five hub genes (CPVL, AADAC, BCAT1, CPXM1, and FBN1). Among them, CPVL exhibited the highest diagnostic accuracy (AUC = 0.895) and the strongest correlation with poor overall survival, and was therefore selected for mechanistic investigation. CPVL expression was markedly upregulated in GC tissues and cell lines. Functional assays demonstrated that CPVL promotes GC cell proliferation and accelerates G1/S-phase transition. Mechanistically, CPVL activated the JAK2/STAT3 signaling pathway, upregulating Cyclin D1 and CDK4 while downregulating p27. Treatment with the JAK2 inhibitor AZD1480 partially reversed these effects. In vivo, CPVL knockdown significantly inhibited tumor growth. CONCLUSION: Through systematic multi-cohort integration and machine-learning prioritization, CPVL was identified as a novel oncogenic driver in gastric cancer. CPVL promotes tumor growth via activation of the JAK2/STAT3 pathway and regulation of the Cyclin D1/CDK4/p27 axis, highlighting its potential as a diagnostic biomarker and therapeutic target.
Entry into the cell cycle requires activation of G1 cyclin-dependent kinases (CDKs) and the G1/S transcriptional program. In fission yeast, the MBF complex is the main transcription factor driving early cell-cycle gene expression. MBF-dependent transcription is activated in metaphase and repressed at the end of S phase by a feedback loop involving the cyclin Cig2 and co-repressors Nrm1 and Yox1. While replicative stress inactivates Yox1 via phosphorylation, the mechanism that activates MBF during an unperturbed cell cycle remains unclear. Here, we identify Nrm1 as the key target of cell cycle regulation in a two-step control mechanism. First, CDK1 phosphorylates Nrm1 in metaphase, leading to its release-along with Yox1-from chromatin. Second, unphosphorylated Nrm1, generated either by dephosphorylation or de novo synthesis, is degraded during anaphase, preventing its re-association with MBF until the end of the next S phase. Together, these parallel pathways create a precisely timed window of MBF activation, ensuring proper cell cycle progression and preserving genomic stability.
Gehua Hugan Gao (GHHGG) is a traditional Chinese medicine paste that is chiefly used to treat liver cancer. However, the potential impact of GHHGG on liver cancer remains unclear. We explored how GHHGG treats liver cancer using bioinformatics, network pharmacology, and molecular docking. Network pharmacology included GHHGG active ingredients, predicted targets, predicted targets for liver cancer, and differential gene collection. A protein-protein interaction network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and crucial targets were ranked according to their degree values. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of liver cancer targets were followed by survival, differential analysis, and molecular docking. Venn diagrams show 123 predicted GHHGG targets for the treatment of hepatocellular carcinoma (HCC). Enrichment analysis showed that GHHGG treats HCC through multiple targets and pathways. We also found that estrogen receptor 1, cytochrome P450 3A4, cyclin-dependent kinase 4, type IIA topoisomerase, aurora kinase A, and cyclin E1 targets were closely associated with HCC development through survival and differential analyses. Molecular docking confirmed GHHGG's strong affinity for liver cancer targets. This study helps us understand GHHGG ingredients and targets for liver cancer treatment. To a certain extent, the molecular mechanism of GHHGG in the treatment of liver cancer has been elucidated, thus providing a theoretical basis.
Floral organ identity is controlled largely by the combinatorial action of MADS domain homeotic transcription factors. Lodicules are specialized plant organs in cereals and grasses that are involved in floret opening and facilitate pollination and fertility in rice (Oryza sativa L.). To understand the mechanisms underlying the specification of the rice lodicule, we investigated the developmental functions of the rice PISTILLATA (PI) paralogs, OsMADS2, and OsMADS4. Null osmads2 mutants reiterated OsMADS2 nonredundant lodicule specification roles and revealed new roles in flowering time and floral organ number and fate. Doubly perturbed osmads2 osmads4kd florets had severe abnormalities, were female infertile, yet could initiate parthenocarpy. Ubiquitous OsMADS4 overexpression rescued osmads2 abnormalities. We also utilized genome-wide binding analyses and transcriptome profiling to identify putative target genes contributing to OsMADS2 functions. In osmads2d8/d8 null mutant, we observed deregulated genes in a plethora of processes including lodicule and stamen development, floral organ number, and cell wall development. Some examples are cell division regulators (Cyclin D6, Cyclin-P4-1-like), an aquaporin (PIP1A), a peptide transporter, a vascular developmental regulator (HOX1), and a cell wall modulator (GH9B16). The deregulation of these genes may be associated with the disrupted cell division, tissue differentiation, and physiology of the malformed lodicules in osmads2 and osmads2 osmads4kd florets. Altogether, we reveal novel roles for the rice PI paralogs in flowering time, panicle exsertion, and embryo sac differentiation, identify gene targets for lodicule development, and provide mechanistic insights on the functional diversification of rice PI paralogs.
PURPOSE: The short lifespan of primary normal choroidal melanocytes (NCMs) in vitro represents a major barrier to mechanistic, functional, and translational studies of choroid biology and uveal melanoma (UM). This study aimed to establish and characterize immortalized human NCM lines that retain melanocytic function, maintain a non-cancerous profile, and are amenable to gene editing. METHODS: NCMs from four donors were immortalized by lentiviral transduction of cyclin-dependent kinase 4 (CDK4R24C), cyclin D1, and human telomerase reverse transcriptase (hTERT), establishing NCM-K4DT lines. Their morphology, melanocytic marker expression, proliferation, and functional properties (melanin synthesis and tyrosinase activity) were evaluated. Genomic stability was assessed by targeted mutation profiling, karyotyping, and copy number variation (CNV) analysis. The tumorigenicity was tested in immunodeficient mice. Plasmid-based CRISPR/Cas9 editing was performed to determine their suitability for gene editing. RESULTS: NCM-K4DT lines retained dendritic-shaped morphology, pigmentation, and expression of PMEL, TYRP1, Melan-A, and SOX10. Cells exhibited enhanced proliferative capacity with preserved cell cycle regulation. Melanin production and tyrosinase activity were comparable to primary NCMs. Genomic profiling confirmed the absence of UM-associated driver mutations and chromosomal abnormalities. In vivo growth assays demonstrated that NCM-K4DT lines did not form tumors within the 3-month observation period. Notably, NCM-K4DT cells were efficiently edited by CRISPR/Cas9. CONCLUSIONS: NCM-K4DT lines represent stable, non-cancerous, and genetically tractable models for studying choroidal melanocyte biology, modeling UM-associated mechanisms, and advancing therapeutic development in ocular research.
Pediatric sarcomas comprise approximately 10% of all childhood solid malignancies and are characterized by distinct genetic and proteomic alterations that have potential diagnostic, prognostic, and therapeutic significance. We have utilized digital spatial profiling (DSP) to identify protein expression in pediatric Ewing sarcoma (ES), Osteosarcoma (OS), Alveolar rhabdomyosarcoma (ARMS), and Embryonal rhabdomyosarcoma (ERMS), in association with clinical outcomes. Formalin-fixed, paraffin-embedded sections from a tissue microarray block containing eight ES, eight OS, five ARMS, and three ERMS cases were subjected to proteomic DSP on a GeoMx NanoString platform yielding information on expression of 580 proteins. Proteins related to epigenetic regulation, signaling pathways, and mesenchymal differentiation were broadly expressed across all tumor types. Tumor-specific protein profiles were defined based on highly expressed proteins. Differentially expressed proteins include Cyclin D1 in ES, S100A4 in OS and IKKi/IKKe in ARMS and ERMS. Immunohistochemical validation confirmed variable expression of H3K27me3 across the tumors, and elevated expression of Cyclin D1 in ES and S100 in OS. These findings underscore the utility of DSP as a high-resolution proteomic tool for the identification of clinically relevant biomarkers in pediatric sarcomas. The results provide a foundation for further investigation of candidate proteins with potential diagnostic, prognostic, and therapeutic applications.