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Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.

Notch signaling dysregulation encourages breast cancer progression through different mechanisms such as stem cell maintenance, cell proliferation and migration/invasion. Furthermore, Notch is a crucial driver regulating juxtracrine and paracrine communications between tumor and stroma. The complex interplay between the abnormal Notch pathway orchestrating the activation of other signals and cellular heterogeneity contribute towards remodeling of the tumor microenvironment. These changes, together with tumor evolution and treatment pressure, drive breast cancer drug resistance. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance, reducing or eliminating breast cancer stem cells. In the present review, we will summarize the current scientific evidence that highlights the involvement of Notch activation within the breast tumor microenvironment, angiogenesis, extracellular matrix remodeling, and tumor/stroma/immune system interplay and its involvement in mechanisms of therapy resistance.

The NOTCH signaling pathway plays an important role in regulating various biological processes, including lineage specification and apoptosis. Multiple components of the NOTCH pathway have been identified in mammalian preimplantation embryos. However, the precise role of the NOTCH pathway in early embryonic development is poorly understood, especially in large animals. Here, we show that the expression of genes encoding key transcripts of the NOTCH pathway is dynamic throughout early embryonic development. We also confirm the presence of active NOTCH1 and RBPJ. By using pharmacological and RNA interference tools, we demonstrate that the NOTCH pathway is required for the proper development of bovine early embryos. This functional consequence could be partly attributed to the major transcriptional mediator, Recombination Signal Binding Protein For Immunoglobulin Kappa J Region (RBPJ), whose deficiency also compromised the embryo quality. Indeed, both NOTCH1 and RBPJ knockdown cause a significant increase of histone H3 serine 10 phosphorylation (pH3S10, a mitosis marker) positive blastomeres, suggesting a cell cycle arrest at mitosis. Importantly, RNA sequencing analyses reveal that either NOTCH1 or RBPJ depletion triggers a reduction in H1FOO that encodes the oocyte-specific linker histone H1 variant. Interestingly, depleting H1FOO results in detrimental effects on the developmental competence of early embryos, similar with NOTCH1 inhibition. Overall, our results reveal a crucial role for NOTCH pathway in regulating bovine preimplantation development, likely by controlling cell proliferation and maintaining H1FOO expression. Summary sentence NOTCH signaling pathway plays an indispensable role in bovine early embryonic development, which is potentially mediated by regulation of cell proliferation and expression of H1FOO.

Ageing profoundly changes our immune system and is thought to be a driving factor in the morbidity and mortality associated with infectious disease in older people. We have previously shown that the impaired immunity to vaccination that occurs in aged individuals is partly attributed to the effect of age on T follicular helper (Tfh) cell formation. In this study, we examined how age intrinsically affects Tfh cell formation in both mice and humans. We show increased formation of Tfh precursors (pre‐Tfh) but no associated increase in germinal centre (GC)‐Tfh cells in aged mice, suggesting age‐driven promotion of only early Tfh cell differentiation. Mechanistically, we show that ageing alters TCR signalling which drives expression of the Notch‐associated transcription factor, RBPJ. Genetic or chemical modulation of RBPJ or Notch rescues this age‐associated early Tfh cell differentiation, and increased intrinsic Notch activity recapitulates this phenomenon in younger mice. Our data offer mechanistic insight into the age‐induced changes in T‐cell activation that affects the differentiation and ultimately the function of effector T cells. Ageing alters TCR signalling which drives expression of the Notch‐associated transcription factor, RBPJ. This results in enhanced differentiation into T follicular helper cell precursors.

Bladder cancer (BC) is one of the most prevalent malignancies worldwide, but it lacks effective targeted therapy due to its elusive molecular mechanism. Therefore, it is important to further investigate the molecular mechanisms that mediate BC progression. By performing a tumor tissue–based gene microarray and shRNA library screening, we found that recombination signal binding protein for immunoglobulin kappa J region (RBPJ) interacting and tubulin associated 1 (RITA1) is crucial for the growth of BC cells. Moreover, RITA1 is aberrantly highly expressed in BC tissues and is also correlated with poor prognosis in patients with BC. Mechanistically, we determined that RITA1 recruits tripartite motif containing 25 (TRIM25) to ubiquitinate RBPJ to accelerate its degradation via proteasome, which leads to the transcriptional inhibition of Notch1 downstream targets. Our results suggest that aberrant high expression of RITA1 drives the growth of BC cells via the RITA1/TRIM25/RBPJ axis and RITA1 may serve as a promising therapeutic target for BC. We demonstrated that aberrant upregulation of RITA1 is crucial for maintaining the growth of BC cells by inhibiting Notch1 signaling. More importantly, we determined, for the first time, a novel mechanism whereby RITA1 recruits TRIM25 to ubiquitinate RBPJ to accelerate its proteasomal degradation, which leads to the transcriptional inhibition of Notch1 downstream targets.

Angiogenesis, the formation of new blood vessels, is tightly regulated by gene transcriptional programs. Yin Ying 1 (YY1) is a ubiquitously distributed transcription factor with diverse and complex biological functions; however, little is known about the cell-type-specific role of YY1 in vascular development and angiogenesis. Here we report that endothelial cell (EC)-specific YY1 deletion in mice led to embryonic lethality as a result of abnormal angiogenesis and vascular defects. Tamoxifen-inducible EC-specific YY1 knockout (YY1iΔEC ) mice exhibited a scarcity of retinal sprouting angiogenesis with fewer endothelial tip cells. YY1iΔEC mice also displayed severe impairment of retinal vessel maturation. In an ex vivo mouse aortic ring assay and a human EC culture system, YY1 depletion impaired endothelial sprouting and migration. Mechanistically, YY1 functions as a repressor protein of Notch signaling that controls EC tip-stalk fate determination. YY1 deficiency enhanced Notch-dependent gene expression and reduced tip cell formation. Specifically, YY1 bound to the N-terminal domain of RBPJ (recombination signal binding protein for Ig Kappa J region) and competed with the Notch coactivator MAML1 (mastermind-like protein 1) for binding to RBPJ, thereby impairing the NICD (intracellular domain of the Notch protein)/MAML1/RBPJ complex formation. Our study reveals an essential role of endothelial YY1 in controlling sprouting angiogenesis through directly interacting with RBPJ and forming a YY1-RBPJ nuclear repression complex.

Abnormal infiltration and activation of monocyte-derived macrophages (moMFs) contribute significantly to thoracic aortic dissection (TAD). The transcription factor RBPJ mediates canonical Notch signaling and modulates macrophage activation, but the role and mechanism of RBPJ in macrophages in TAD remains unclear. Here, we show that RBPJ was upregulated in macrophages infiltrating the aorta in TAD patients and BAPN-induced mouse model. Myeloid-specific Rbpj ablation protected mice from TAD, reducing death, aortic damage, macrophage infiltration, and M1-like polarization while enhancing M2-like polarization. Because moMFs dominate aorta as shown in public scRNA-seq data, and RBPJ is upregulated in moMFs compared with blood monocytes/macrophages, we assumed that mechanical force, specifically cyclic stretch, might be one of the environmental cues of macrophage activation in aorta. Indeed, bone marrow-derived macrophages (BMDMs) loaded with cyclic stretch upregulated RBPJ expression in a Piezo1-dependent way, accompanied by increased M1-like polarization, and Rbpj ablation cancelled the force-induced M1-like polarization. By RNA-sequencing, we found that cyclic stretch induced a metabolic reprogram of BMDMs characterized by upregulation of glycolysis-related genes and HIF1α, which was dependent on RBPJ. Further analyses showed that cyclic stretch upregulated PDK1, a negative regulator of pyruvate dehydrogenase (PDH), which was abrogated by RBPJ deficiency. Based on these findings, we administered dichloroacetate (DCA), a pan-PDK inhibitor, in TAD mice, and found that DCA significantly attenuated BAPN-induced TAD in mice. Therefore, our results demonstrate that RBPJ is required for pro-inflammatory moMFs activation, likely by mediating mechanotransduction-induced glycolysis via PDK1 upregulation, and PDK1 inhibitors such as DCA are potential therapeutics for TAD.

Epstein–Barr virus is a globally disseminated oncovirus capable of causing various malignancies, including gastric cancer, Burkitt lymphoma, and Hodgkin’s lymphoma. The influence of recombination on the EBV genome revealed limitations in the current traditional EBV classification, and the extent of these recombination events across the EBV genome is not fully understood. The nuclear antigen 3C (EBNA3C) is an indispensable gene in the oncogenesis of the virus. Despite its critical role, little is known about EBNA3C sequence variability. We examined 988 EBNA3C gene sequences extracted from EBV genomes in this context. Among the protein motifs, the interaction sites with Nm23-H1, RBP-Jk, and nuclear localization signal (NLS) 2 and 3 were the most divergent between EBV types, while NLS-1 and the leucine zipper-like showed high conservation. In our study of the impact of recombination vs. point mutations in the EBNA3C gene, we found that recombination contributed five times more to substitutions than mutation. Notably, Asian populations exhibited the highest variability and recombination rates. Importantly, our analysis revealed geographical rather than disease-specific markers. Furthermore, filtering for recombination regions did not affect the classical classification of EBV-1 and EBV-2. This finding suggests that recombination is pivotal in the architecture of EBV genetic diversity of the EBNA3C gene.

Short-term starvation (STS) has been shown to enhance the sensitivity of tumors to chemotherapy while concurrently safeguarding normal cells from its detrimental side effects. Nonetheless, the extent to which STS relies on the anti-tumor immune response to impede the progression of hepatocellular carcinoma (HCC) remains uncertain. In this study, we employed mass cytometry, flow cytometry, immunoprecipitation, immunoblotting, CUT&Tag, RT-qPCR, and DNA pull-down assays to evaluate the relationship between STS and T-cell antitumor immunity in HCC. We demonstrated that STS alleviated T cell exhaustion in HCC. This study elucidated the mechanism by which STS blocked CD36 N-glycosylation, leading to the upregulation of AMPK phosphorylation and the downregulation of USP7 UFMylation, thus enhancing ubiquitination and destabilized USP7. Consequently, diminished USP7 levels facilitated the ubiquitination and subsequent degradation of RBPJ, thereby inhibiting T cell exhaustion through the IRF4/TNFRSF1B axis. From a therapeutic standpoint, STS not only suppressed the growth of patient-derived orthotopic xenografts but also enhanced their sensitivity to immunotherapy. These findings uncovered a novel mechanism by which N-glycosylation participated in UFMylation/ubiquitination to regulate T cell exhaustion, and we underscored the potential of targeting USP7 and RBPJ in anti-tumor immunotherapy strategies.

Elaboration of protocols for differentiation of human pluripotent stem cells to dopamine neurons is an important issue for development of cell replacement therapy for Parkinson’s disease. A number of protocols have been already developed; however, their efficiency and specificity still can be improved. Investigating the role of signaling cascades, important for neurogenesis, can help to solve this problem and to provide a deeper understanding of their role in neuronal development. Notch signaling plays an essential role in development and maintenance of the central nervous system after birth. In our study, we analyzed the effect of Notch activation and inhibition at the early stages of differentiation of human induced pluripotent stem cells to dopaminergic neurons. We found that, during the first seven days of differentiation, the cells were not sensitive to the Notch inhibition. On the contrary, activation of Notch signaling during the same time period led to significant changes and was associated with an increase in expression of genes, specific for caudal parts of the brain, a decrease of expression of genes, specific for forebrain, as well as a decrease of expression of genes, important for the formation of axons and dendrites and microtubule stabilizing proteins.