ZNF750 is a lineage-specific tumour suppressor in squamous cell carcinoma.

ZNF750 controls epithelial homeostasis by regulating epidermal-differentiation genes, a role underscored by its pathogenic mutations in esophageal squamous cell cancers (SCCs). However, the precise role of ZNF750 in SCC cell biology remains unclear. In this study, we report that ZNF750 is exclusively deleted, mutated and underexpressed in human SCCs, and low ZNF750 expression is associated with poor survival. Restoration of wildtype, but not mutant ZNF750 protein uniquely inhibited the malignant phenotypes of SCC cells both in vitro and in vivo. Notably, ZNF750 promoted the expression of a long non-coding RNA (TINCR), which mediated both cancer-inhibition and differentiation-induction effects of ZNF750. In addition, ZNF750 potently suppressed cell migration by directly inhibiting the transactivation of LAMC2. Together, our findings characterize ZNF750 as a crucial SCC-specific suppressor and uncover its novel anticancer-associated functions

Nucleoporin Nup58 Localizes to Centrosomes and Mid-Bodies During Mitosis

Background: Nuclear pore complexes (NPCs) act as nano-turnstiles within nuclear membranes between the cyto- plasm and nucleus of mammalian cells. NPC proteins, called nucleoporins (Nups), mediate trafficking of proteins and RNA into and out of the nucleus, and are involved in a variety of mitotic processes. We previously reported that Nup62 localizes to the centrosome and mitotic spindle during mitosis, and plays a role in centrosome homeostasis.However, whether Nup58, a Nup62 subcomplex protein, also localizes to spindle poles is unknown. Result: Herein, we show that Nup58 localizes to the nuclear rim during interphase, and to mitotic spindles, cen- trosomes, and midbodies during mitosis. Our confocal microscopy, live-cell imaging, and stimulated emission deple- tion nanoscopy results also demonstrated that Nup58 localized to the centrosomes during metaphase and relocalized to midbodies during abscission. Depletion of Nup58 resulted in centrosomal abnormalities and delayed abscission. Conclusion: Nup58 localized at the centrosomes and mitotic spindle during metaphase and relocalized at midbod- ies during abscission. This study highlights the important role of Nup58 in mitosi

The role of nucleoporin Nup58 during mitosis

Nuclear pore complexes (NPCs) are transport channels between the nucleus and the cytoplasm. The NPCs are composed by around 30 different proteins, termed nucleoporins (Nups) and each Nup is present in multiple copies. Recently, we and others discovered that several nucleoporins play critical roles during cell division including chromosome condensation, sister chromatid cohesion, kinetochore assembly and spindle formation. Nup58 is a part of the central transport channel of the NPC, which forms a complex protein with other nucleoporins such as Nup62 and Nup54. Recently, we showed that Nup62 plays a novel role in centrosome integrity. Here, we show that Nup62 interacts with Nup58 during cell mitosis. Next, we performed RNA interference-mediated knockdown of Nup58. Currently, we are investigating nup58 depletion effect in cell cycle

Structure–activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells

The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C20-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC50 values against A549 cells ranged from 1.72 to 5.44 μM. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest

The role of nucleoporin Nup58 during cell division

Nuclear pore complexes (NPCs) are transport channels between the nucleus and the cytoplasm. The NPCs are composed by around 30 different proteins, termed nucleoporins (Nups) and each Nup is present in multiple copies. Recently, we and others discovered that several nucleoporins play critical roles during cell division including chromosome condensation, sister chromatid cohesion, kinetochore assembly and spindle formation. Nup58 is a part of the central transport channel of the NPC, which forms a complex protein with other nucleoporins such as Nup62 and Nup54. Recently, we showed that Nup62 plays a novel role in centrosome integrity. Here, we show that Nup62 interacts with Nup58 during cell mitosis. Next, we performed RNA interference-mediated knockdown of Nup58. Currently, we are investigating Nup58 depletion effect in cell cycle

THE SPATIOTEMPORAL DYNAMICS OF NUCLEOPORIN NUP58 DURING CELL DIVISION

Nuclear pore complexes (NPCs) are transport channels between the nucleus and the cytoplasm. The NPCs are composed by around 30 Nuclear pore complexes (NPCs) are transport channels between the nucleus and the cytoplasm. The NPCs are composed by around 30 different proteins, termed nucleoporins (Nups) and each Nup is present in multiple copies. Recently, we and others discovered that several nucleoporins play critical roles during cell division including centrosome integrity, kinetochore assembly, spindle formation and orientation. Nup58 is a part of the central transport channel of the NPC, which forms a complex protein with other nucleoporins such as Nup62 and Nup54. Where Nup58 localize and what their roles during cell division are still poorly understood. Here, we show that Nup58 localizes at the Nuclear pore complexes (NPCs) are transport channels between the nucleus and the cytoplasm. The NPCs are composed by around 30 different proteins, termed nucleoporins (Nups) and each Nup is present in multiple copies. Recently, we and others discovered that several nucleoporins play critical roles during cell division including centrosome integrity, kinetochore assembly, spindle formation and orientation. Nup58 is a part of the central transport channel of the NPC, which forms a complex protein with other nucleoporins such as Nup62 and Nup54. Where Nup58 localize and what their roles during cell division are still poorly understood. Here, we show that Nup58 localizes at the centrosome during prophase to metaphase, interacting with Nup62, Nup54 and also two centrosome marker protein gamma tubulin and SAS6. Depletion of Nup58 leads to monopolar spindle formation, multi-nucleic cell formation, and delayed cytokinesis. We suggest that Nup58 may regulate cytokinesis abscission. Our study gives novel insight into the role of Nup58 in cell division. centrosome during prophase to metaphase, interacting with Nup62, Nup54 and also two centrosome marker protein gamma tubulin and SAS6. Depletion of Nup58 leads to monopolar spindle formation, multi-nucleic cell formation, and delayed cytokinesis. We suggest that Nup58 may regulate cytokinesis abscission. Our study gives novel insight into the role of Nup58 in cell division. different proteins, termed nucleoporins (Nups) and each Nup is present in multiple copies. Recently, we and others discovered that several nucleoporins play critical roles during cell division including centrosome integrity, kinetochore assembly, spindle formation and orientation. Nup58 is a part of the central transport channel of the NPC, which forms a complex protein with other nucleoporins such as Nup62 and Nup54. Where Nup58 localize and what their roles during cell division are still poorly understood. Here, we show that Nup58 localizes at the centrosome during prophase to metaphase, interacting with Nup62, Nup54 and also two centrosome marker protein gamma tubulin and SAS6. Depletion of Nup58 leads to monopolar spindle formation, multi-nucleic cell formation, and delayed cytokinesis. We suggest that Nup58 may regulate cytokinesis abscission. Our study gives novel insight into the role of Nup58 in cell division

Nucleoporin TPR (Translocated Promoter Region, Nuc;ear Basket Protein) Upregulation Alters MTOR-HSF1 Trails adn Suppresses Autophagy Induction in Ependymoma

Children with ependymoma have high mortality rates because ependymoma is resistant to conventional theraphy. Genomic and transptomic studies have identified potential targets as significantly altered reported, the detailed mechanisms for the roles of these candidate oncogenes in ependymoma progression remain unclear. Here, we report an oncogenic role of the nucleoporin TPR (Translocated promoter region, nuclear basket protein) in regulating HSF1 (Heat Shock Transcription Factor 1) mRNA trafficking, maintaining MTORC1 activity to phosphorylate ULK1, and praventing macroautophagy/autophagy induction in ependymoma. High expression of TPR were associates with inreased HSF1 and HSPA/HSP70 expression in ependymoma patients. In an ependymoma mouse xenohraft model, MTOR inhibition by rapamycin therapeutically suppressed TPR expression and reduced tumor size in vivo. Togetherm these results suggest that TPR may act as a biomarker for ependymoma, and pharmacological interventions targeting TPR-HSF1-MTOR may have therapeutic potential for ependymoma treatment

Direct visualization of avian influenza H5N1 hemagglutinin precursor and its conformational change by high-speed atomic force microscopy

Hemagglutinin (HA) of influenza A is one of the key virulence factors that mediates the release of viral components in host cells. HA is initially synthesized as a trimeric precursor (HA0) and then it is cleaved by proteases to become a functional HA. Low pH induces irreversible conformational changes in both HA0 and HA but only HA is fusion compatible. Here, we used high-speed atomic force microscopy (HS-AFM) to record conformational changes in HA0 trimers (H5N1) from neutral to acidic conditions at a millisecond scale. Methods: Purified HA0 protein was diluted with either neutral Tris-HCl (pH 7.4) or acetic acid-titrated Tris-HCl(pH 5.0) and then loaded onto bare mica. Neutral or acidic Tris-HCl was used as the scanning buffer. HS-AFM movies were recorded and processed using Image J software. Results: The conformation of HA0neutral visualized using HS-AFM was comparable to the HA trimer structures depicted in the PDB data and the AFM simulator. HA0 underwent rapid conformational changes under low pH condition. The circularity and area of HA0acid were significantly higher than in HA0neutral. In contrast, the height of HA0acid was significantly lower than in HA0neutral. Conclusions: We have captured real-time images of the native HA0 trimer structure under physiological conditions using HS-AFM. By analyzing the images, we confirm that HA0 trimer is sensitive to acidic conditions. General significance: The dynamic nature of the HA structure, particularly in the host endosome, is essential for H5N1 infectivity. Understanding this acidic behavior is imperative for designing therapeutic strategies against H5N1. This article reports a sophisticated new tool for studying the spatiotemporal dynamics of the HA precursor protein

Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites

The p300 and CBP histone acetyltransferases are recruited to DNA double-strand break (DSB) sites where they induce histone acetylation, thereby influencing the chromatin structure and DNA repair process. Whether p300/CBP at DSB sites also acetylate non-histone proteins, and how their acetylation affects DSB repair, remain unknown. Here we show that p300/CBP acetylate RAD52, a human homologous recombination (HR) DNA repair protein, at DSB sites. Using in vitro acetylated RAD52, we identified 13 potential acetylation sites in RAD52 by a mass spectrometry analysis. An immunofluorescence microscopy analysis revealed that RAD52 acetylation at DSBs sites is counteracted by SIRT2- and SIRT3-mediated deacetylation, and that non-acetylated RAD52 initially accumulates at DSB sites, but dissociates prematurely from them. In the absence of RAD52 acetylation, RAD51, which plays a central role in HR, also dissociates prematurely from DSB sites, and hence HR is impaired. Furthermore, inhibition of ataxia telangiectasia mutated (ATM) protein by siRNA or inhibitor treatment demonstrated that the acetylation of RAD52 at DSB sites is dependent on the ATM protein kinase activity, through the formation of RAD52, p300/CBP, SIRT2, and SIRT3 foci at DSB sites. Our findings clarify the importance of RAD52 acetylation in HR and its underlying mechanism