The eukaryotic cell cycle is controlled by a complex regulatory network, which is still poorly understood. Here we demonstrate that TRPS1, an atypical GATA factor, modulates cell proliferation and controls cell cycle progression. Silencing TRPS1 had a differential effect on the expression of nine key cell cycle-related genes. Eight of these genes are known to be involved in the regulation of the G2 phase and the G2/M transition of the cell cycle. Using cell synchronization studies, we confirmed that TRPS1 plays an important role in the control of cells in these phases of the cell cycle. We also show that silencing TRPS1 controls the expression of 53BP1, but not TP53. TRPS1 silencing also decreases the expression of two histone deacetylases, HDAC2 and HDAC4, as well as the overall HDAC activity in the cells, and leads to the subsequent increase in the acetylation of histone4 K16 but not of histone3 K9 or K18. Finally, we demonstrate that TRPS1 expression is elevated in luminal breast cancer cells and luminal breast cancer tissues as compared with other breast cancer subtypes. Overall, our study proposes that TRPS1 acts as a central hub in the control of cell cycle and proliferation during cancer development.
Purpose Vaccines play important roles in antitumor biotherapy. Autophagy in tumor cells plays a critical role in depredating proteins, including tumor-specific antigens and tumor-associated antigens. We aimed to induce and collect tumor-derived autophagosomes (DRibbles) from tumor cells as a novel antitumor vaccine by inhibiting the functions of proteasomes and lysosomes. Materials and methods DRibbles were prepared and their morphological and autophagic properties characterized. Dendritic cells (DCs) generated from the bone marrow monocytes of mice were cocultured with DRibbles, then surface molecules of DCs and B cells, as well as apoptosis of DCs, were determined by flow cytometry. Meanwhile, functional properties of the DRibble-DCs were examined by mixed lymphocyte reactions and animal experiments. Results The diameter of autophagic nanoparticles with spherical and double-membrane structure was between 200 nm and 500 nm. DRibbles resulted in the upregulation of costimulatory molecules CD40 and CD86 as well as major histocompatibility complex (MHC)-I molecules on DCs, but not MHC-II. The expressions of CD40, CD80, and CD86 and that of MHC-II molecules on B cells were also upregulated. Moreover, suppression of tumor growth and lifetime prolongation was observed in DRibble-DC-vaccinated tumor-bearing mice. Conclusion Our results demonstrate that naïve T cells can be activated effectively by DC cross-presenting antigens on upregulated MHC-I, suggesting that DRibbles be deployed as an effective antitumor vaccine for head and neck cancer immunotherapy in clinical trials.
The roles of the MYC transcription factor in transcriptional regulation have been studied intensively. However, the general mechanism underlying the recruitment of MYC to chromatin is less clear. Here, we found that the Krüppel-like transcription factor ZFP281 plays important roles in recruiting MYC to active promoters in mouse embryonic stem cells. At the genome scale, ZFP281 is broadly associated with MYC, and the depletion of ZFP281 significantly reduces the levels of MYC and RNA polymerase II at the ZFP281- and MYC-cobound genes. Specially, we found that recruitment is required for the regulation of the Lin28a oncogene and pri-let-7 transcription. Our results therefore suggest a major role of ZFP281 in recruiting MYC to chromatin and the integration of ZFP281 and the MYC/LIN28A/Let-7 loop into a multilevel circuit.
BackgroundsDespite continuing progress in X-ray crystallography and high-field NMR spectroscopy for determination of three-dimensional protein structures, the number of unsolved and newly discovered sequences grows much faster than that of determined structures. Protein modeling methods can possibly bridge this huge sequence-structure gap with the development of computational science. A grand challenging problem is to predict three-dimensional protein structure from its primary structure (residues sequence) alone. However, predicting residue contact maps is a crucial and promising intermediate step towards final three-dimensional structure prediction. Better predictions of local and non-local contacts between residues can transform protein sequence alignment to structure alignment, which can finally improve template based three-dimensional protein structure predictors greatly.MethodsCNNcon, an improved multiple neural networks based contact map predictor using six sub-networks and one final cascade-network, was developed in this paper. Both the sub-networks and the final cascade-network were trained and tested with their corresponding data sets. While for testing, the target protein was first coded and then input to its corresponding sub-networks for prediction. After that, the intermediate results were input to the cascade-network to finish the final prediction.ResultsThe CNNcon can accurately predict 58.86% in average of contacts at a distance cutoff of 8 Å for proteins with lengths ranging from 51 to 450. The comparison results show that the present method performs better than the compared state-of-the-art predictors. Particularly, the prediction accuracy keeps steady with the increase of protein sequence length. It indicates that the CNNcon overcomes the thin density problem, with which other current predictors have trouble. This advantage makes the method valuable to the prediction of long length proteins. As a result, the effective prediction of long length proteins could be possible by the CNNcon.
Surface modifications can endow nanomaterials with presupposed immunoregulatory functions to optimize vaccine-induced immune responses. In this work, we modified an immunoregulatory molecule, amantadine (Ada), on the outermost layer of PVP-PEG-coated silver nanorods (Ada-PVP-PEG silver nanorods). Such Ada surface-modified silver nanorods promote HIV vaccine-triggered cytotoxic lymphocytes (CTLs) to produce around eightfold stronger tumor necrosis factor alpha (TNF-α) in vivo. The enhancement of HIV-specific CTL-derived TNF-α significantly facilitates the death of HIV-infected cells (from 28.86 to 84.19%) and reduces HIV production (around sixfold). This work supports the critical role of surface modifications of nanomaterials in fundamentally improving the immunotherapy of HIV vaccine against HIV-infected cells.
BackgroundsRecent explosion of biological data brings a great challenge for the traditional clustering algorithms. With increasing scale of data sets, much larger memory and longer runtime are required for the cluster identification problems. The affinity propagation algorithm outperforms many other classical clustering algorithms and is widely applied into the biological researches. However, the time and space complexity become a great bottleneck when handling the large-scale data sets. Moreover, the similarity matrix, whose constructing procedure takes long runtime, is required before running the affinity propagation algorithm, since the algorithm clusters data sets based on the similarities between data pairs.MethodsTwo types of parallel architectures are proposed in this paper to accelerate the similarity matrix constructing procedure and the affinity propagation algorithm. The memory-shared architecture is used to construct the similarity matrix, and the distributed system is taken for the affinity propagation algorithm, because of its large memory size and great computing capacity. An appropriate way of data partition and reduction is designed in our method, in order to minimize the global communication cost among processes.ResultA speedup of 100 is gained with 128 cores. The runtime is reduced from serval hours to a few seconds, which indicates that parallel algorithm is capable of handling large-scale data sets effectively. The parallel affinity propagation also achieves a good performance when clustering large-scale gene data (microarray) and detecting families in large protein superfamilies.
Highlights d Activity blockade by TTX induces rapid and transient release of NGPF2 d NGPF2 is necessary and sufficient for synaptic scaling up d NGPF2 triggers synaptic scaling up through ALK-LIMKcofilin pathway d NGPF2 synthesis requires FMRP1
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