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Microblogs are currently one of the most well-liked social platforms in China, and sentiment analysis of microblog texts can help further analyze the realization of their media value; however, the current task of sentiment analysis based on microblog information suffers from low accuracy due to the large size and high redundancy of microblog data, a microblog sentiment analysis method using Bidirectional Encoder Representation from Transformers (BERT)–Text Convolutional Neural Network (TextCNN)–Bidirectional Gate Recurrent Unit (BiGRU)–Multihead-Attention model in Spark big data environment is proposed. First, the Chinese pre-trained language model BERT is used to convert the input data into dynamic character-level word vectors; then, TextCNN is used to effectively obtain local features such as keywords and pool the filtered features; then, BiGRU is introduced to quickly capture more comprehensive semantic information; finally, a multi-headed attention mechanism is implemented to emphasize the most significant features in order to accomplish the sentiment classification of microblog information task precisely. By comparing the existing advanced models, the proposed model demonstrates an improvement of at least 4.99% and 0.05 in accuracy and F1-score evaluation indexes, respectively. This enhancement significantly enhances the accuracy of microblog sentiment analysis tasks and aids pertinent authorities in comprehending the inclination of individual’s attitude toward hot topics. Furthermore, it facilitates a prompt prediction of topic trends, enabling them to guide public opinion accordingly.

Generally, most miRNAs that were up-regulated during differentiation promoted adipogenesis, but our research indicated that up-regulation of miR-145 in porcine preadipocytes did not promote but inhibit adipogenesis. In this study, miR-145 was significantly up-regulated during porcine dedifferentiated fat (DFAT) cells differentiation. In miR-145 overexpressed DFAT cells, adipogenesis was inhibited and triglycerides accumulation was decreased after hormone stimulation (PCCAAT/enhancer-binding protein α (C/EBPα), and peroxisome proliferator-activated receptor γ2 (PPARγ2). These effects caused by miR-145 overexpression were mediated by Insulin receptor substrate 1 (IRS1) as a mechanism. These data suggested that induced miR-145 expression during differentiation could inhibit adipogenesis by targeting IRS1, and miR-145 may be novel agent for adipose tissue engineering.

The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress (1-6). Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings (7,8), suggesting that the ARF-p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF-p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF-p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress., Although recent studies have demonstrated that ARF turnover can occur through ubiquitylation and proteasomal degradation, the identity of the E3 ligase responsible for ARF degradation and its biological significance are [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.03.037 Byline: Delin Chen (1), Ning Kon (1), Muyang Li (1), Wenzhu Zhang (1), Jun Qin (2), Wei Gu Abstract: Although the importance of the ARF tumor suppressor in p53 regulation is well established, numerous studies indicate that ARF also suppresses cell growth in a p53/Mdm2-independent manner. To understand the mechanism of ARF-mediated tumor suppression, we identified a ubiquitin ligase, ARF-BP1, as a key factor associated with ARF in vivo. ARF-BP1 harbors a signature HECT motif, and its ubiquitin ligase activity is inhibited by ARF. Notably, inactivation of ARF-BP1, but not Mdm2, suppresses the growth of p53 null cells in a manner reminiscent of ARF induction. Surprisingly, in p53 wild-type cells, ARF-BP1 directly binds and ubiquitinates p53, and inactivation of endogenous ARF-BP1 is crucial for ARF-mediated p53 stabilization. Thus, our study modifies the current view of ARF-mediated p53 activation and reveals that ARF-BP1 is a critical mediator of both the p53-independent and p53-dependent tumor suppressor functions of ARF. As such, ARF-BP1 may serve as a potential target for therapeutic intervention in tumors regardless of p53 status. Author Affiliation: (1) Institute for Cancer Genetics, Department of Pathology, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, New York 10032 (2) Departments of Biochemistry and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030 Article History: Received 13 September 2004; Revised 24 February 2005; Accepted 30 March 2005 Article Note: (miscellaneous) Published: June 30, 2005

Results demonstrate that mammalian Sir2alpha interacts with p53 inhibiting deacetylation of p53 as well as enhancing acetylation of p53 in vivo. Data also suggest that Sir2alpha represses p53-dependent apoptosis during DNA damage and oxidative stress.

Author(s): Jianyuan Luo [1]; Fei Su [1]; Delin Chen; Ariel Shiloh; Wei Gu (corresponding author) The p53 tumour suppressor is a transcriptional factor whose activity is modulated by protein stability [...]

The deacetylation and repression of the activity of forkhead transcription factor - Foxo3a and other mammalian forkhead factors by the mammalian SIR2 ortholog SIRT1 is reported. The speculation over the down regulation of the two classes of damage - responsive mammalian factors, favoring longer life - span under specific environmental conditions is presented.

Although Mdm2-mediated ubiquitination is essential for both degradation and nuclear export of p53, the molecular basis for the differential effects of Mdm2 remains unknown. Here we show that low levels of Mdm2 activity induce monoubiquitination and nuclear export of p53, whereas high levels promote p53's polyubiquitination and nuclear degradation. A p53-ubiquitin fusion protein that mimics monoubiquitinated p53 was found to accumulate in the cytoplasm in an MdmZ-independent manner, indicating that monoubiquitination is critical for p53 trafficking. These results clarify the nature of ubiquitination-mediated p53 regulation and suggest that distinct mechanisms regulate p53 function in accordance with the levels of Mdm2 activity. [ABSTRACT FROM AUTHOR]

The N 6 -methyladenosine (m 6 A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m 6 A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). Methylated RNA immunoprecipitation-seq (MeRIP-seq) analyses showed that m 6 A modification peaks were enriched at metabolic pathway-related transcripts in glioma stem cells (GSC) compared with neural progenitor cells. In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m 6 A modification levels of serine- and arginine-rich splicing factors ( SRSF ), which led to YTHDC1-dependent NMD of SRSF transcripts and decreased SRSF protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m 6 A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression. SIGNIFICANCE: These findings establish the oncogenic role of m 6 A writer METTL3 in glioblastoma stem cells., (©2019 American Association for Cancer Research.)

The p53 tumor suppressor is maintained at low levels in normal cells by Mdm2-mediated degradation and strongly stabilized in response to various types of stress including hypoxia. Although hypoxia-inducible factor 1 alpha (HIF-1 alpha) has been implicated to be involved in p53 stabilization, the precise mechanism by which HIF-1 alpha regulates p53-mediated function remains unknown. Here, we found that HIF-1 alpha directly binds Mdm2 both in vitro and in vivo; in contrast, p53 fails to directly interact with HIF-1 alpha in vitro. Interestingly, Mdm2 expression can significantly enhance the in vivo association between p53 and HIF-1 alpha, indicating that Mdm2 may act as a bridge and mediate the indirect interaction between HIF-1 alpha and p53 in cells. Furthermore, HIF-1 alpha protects p53 degradation mediated by Mdm2, and leads to activation of p53-mediated transcription in cells. To elucidate the mechanism of HIF-1 alpha-mediated effect, we also found that HIF-1 alpha can significantly suppress Mdm2-mediated p53 ubiquitination in vitro and blocks Mdm2-mediated nuclear export of p53. These results have significant implications regarding the molecular mechanism by which p53 is activated by HIF-1 alpha in response to hypoxia.