The development of small-molecule inhibitors targeting MYC / 药学学报

The MYC gene, one of the most common dysregulated driver genes in human cancers, is composed of three paralogous genes C-MYC, N-MYC and L-MYC. It is abnormally activated in more than half of cancer types. Since MYC plays an important role in the formation, maintenance and progression of cancer, targeting MYC is an effective strategy for cancer treatment. As a potential anti-cancer target, MYC is considered "undruggable" because it lacks a suitable pocket for accommodating small molecule inhibitors. Recently, under the guidance of protein structure information and many computational tools, many indirect strategies to inhibit MYC have emerged and shown favorable anti-cancer effects in tumor models. In this paper, the recent small molecules that indirectly target MYC are divided into inhibitors acting on the protein-protein interaction (PPI) among MYC and other proteins, and targeting inhibitors regulating MYC action. Additionally, the introduction and assessment towards compounds with different mechanisms are summarized to provide reference for the further research of MYC inhibitors.

Bioinformatics analysis of safflower WD40 transcription factor family genes / 中国中药杂志

The WD40 transcription factor family is a gene superfamily widely found in eukaryotes, which is closely related to plant growth and development regulation. It has been reported that the WD40 transcription factor was involved in the synthesis of anthocyanins, which is one of the vital components of safflower flavonoid compounds. In this study, 40 CtWD40 members in the safflower genome were identified though bioinformatics tools and gene expression analysis methods. According to the WD40 protein sequence and phylogenetic characteristics of Arabidopsis and other plants, the safflower CtWD40 family was classified into 7 subfamilies. Conservative motif analysis was used to reveal the specific conserved motifs and gene structures of each subfamily member, and there exist a certain degree of similarities in the conserved motifs and gene structure between the closely related family members. Subsequently, the search for cis-acting elements of gene promoters found CtWD40-specific promoter elements, revealing the metabolic pathways which may involve. Next, enrichment of function analysis was employed to analyze the functional categories and cellular localization of the CtWD40 protein. Furthermore, the interactions between CtWD40 proteins predicted its potential regulatory function. Finally, 19 members of the safflower CtWD40 subfamily were analyzed by qRT-PCR, the result showed the expression patterns of these members were different in diverse tissue and flowering period. This study provides a basis for the functional and expression research of the CtWD40 genes.

FBXW7 and RhoA / Rho kinase protein expressions are involved in myocardial fibrosis in diabetic rats / 中国药理学与毒理学杂志

Objective To investigate the relationship between the expression of F-box / Protein-containing WD-40 domain protein (FBXW7), Ras homologous family member A (RhoA), Rho-associated coiled coil protein kinase (ROCK) and myocardial fibrosis in diabetes. Methods SD The rats were randomly divided into a normal control group and a diabetes model group, and a disposable ip streptozotocin 60 mg · kg-1 was used to establish a rat model of type 1 diabetes, which was tested at 2, 4, 8, 12, and 16 weeks, respectively. HE staining to observe the morphological changes of rat heart tissue; Masson staining and measurement of myocardial hydroxyproline (HYP) content to observe the degree of myocardial collagen deposition; ELISA to detect serum FBXW7, transforming growth factor β1 (TGF-β1) and connective tissue growth Factor (CTGF) content; Western blotting and immunohistochemical detection of FBXW7, RhoA and ROCK1 protein expression in myocardium. Results The myocardial cells of the diabetic model group were found to have varying degrees of focal myocardial cell degeneration, necrosis, and fibrous tissue. Hyperplasia, etc. Compared with the normal control group, the collagen deposition area and collagen content in the myocardial tissue of the model group rats increased significantly at 4 to 16 weeks (P <0.05, P <0.01), showing an increasing trend; 2 to 4 weeks The content of FBXW7 in the serum of rats increased significantly (P <0.01). It decreased at 8 weeks, but was still significantly higher than the normal control group (P <0.01); at 8 to 16 weeks, the levels of TGF-β1 and CTGF in the serum of rats gradually increased (P <0.01). The results showed that the myocardial RhoA and ROCK1 protein expressions in the model group were significantly higher than those in the normal control group at each time point (P <0.05, P <0.01); the myocardial FBXW7 expression in the model group rats was higher than that in the normal control group at 2 to 12 weeks Significantly increased (P <0.01, P <0.01), with the highest expression at 4 weeks, decreased expression at 8-16 weeks, and negatively correlated with time (r = -0.988, P <0.05), but still higher than the normal control group ( P <0.01). Conclusion FBXW7 and RhoA / Rho kinase are involved in the development of myocardial fibrosis in diabetic rats and may become targets for the treatment of diabetic cardiomyopathy.

Msi1-Like (MSIL) Proteins in Fungi

Msi1-like (MSIL) proteins, which are eukaryote-specific and contain a series of WD40 repeats, have pleiotropic roles in chromatin assembly, DNA damage repair, and regulation of nutrient/stress-sensing signaling pathways. In the fungal kingdom, the functions of MSIL proteins have been studied most intensively in the budding yeast model Saccharomyces cerevisiae, an ascomycete. Yet their functions are largely unknown in other fungi. Recently, an MSIL protein, Msl1, was discovered and functionally characterized in the pathogenic yeast Cryptococcus neoformans, a basidiomycete. Interestingly, MSIL proteins appear to have redundant and unique roles in both fungi, suggesting that MSIL proteins may have evolutionarily divergent roles in different parts of the fungal kingdom. In this review, we will describe the current findings regarding the role of MSIL proteins in fungi and discuss future directions for research on this topic.

Metacercarial proteins interacting with WD40-repeat protein of Clonorchis sinensis

The WD40-repeat proteins serve as a platform coordinating partner proteins and are involved in a range of regulatory cellular functions. A WD40-repeat protein (CsWD1) of Clonorchis sinensis previously cloned is expressed stage-specifically in the tegumental syncytium of C. sinensis metacercariae. In the present study, interacting proteins with the CsWD1 protein was purified by immunoprecipitation and 2 dimension gel electrophoresis from the C. sinensis metacercaria soluble extract, and tryptic peptides were analyzed by LC/ESI-MS. Putative partner proteins were annotated to be actin-2, glyceraldehyde-3-phosphate dehydrogenase, and hypothetical and unmanned proteins. The CsWD1 protein was predicted to contain 3 conserved actin-interacting residues on its functional surface. With these results, the CsWD1 protein is suggested to be an actin-interacting protein of C. sinensis.

Distribution Change of WD40 Repeat Protein 1 in Artificially Induced Senescent PC12 Cells

Background: WDR1 is thought to be correlating with polymerization and depolymerization of actin protein. Though WDR1 was found to be within nucleus, in which actin could not be present by previous studies, the exact distribution pattern of WDR1 protein under various circumstances was not elucidated up to the present time. In this regard, we tried to see a change in the distribution of WDR1 protein within artificially induced senescent PC 12 pheochromocytoma cells for the first time. Methods: PC12 pheochromocytoma cells (ATCC CRL-1721) were grown in the culture media including 1 micrometer 3'-Azido-3'-deoxythymidine (AZT, Sigma-Aldrich, USA). The senescence of the cells was confirmed by senescence detection kit (Calbiochem, San Diego, CA). Immunocytochemical study by using WDR1 antibody was also performed in the cells treated with AZT during 0, 75 and 153 days. Results: WDR1 protein was mainly observed within the cytoplasm of the cells not treated with AZT. However, the distribution of the same protein was changed into the nucleus after 153 day-AZT treatment. Conclusion: The distribution of WDR1 protein was changed into nucleus in the artificially senescent PC12 cells.

Progress in Structural and Functional Study of Ubiquitin Ligases / 生物化学与生物物理进展

Ubiquitination on target proteins is the signal of cellular protein degradation.Ubiquitin ligase E3 is one of the key enzymes in ubiquitination,it recognizes a specific substrate protein and recruits an ubiquitin conjugating enzyme E2,mediating the ubquitin transfer from the E2 to the substrate protein.Ubiquitin ligase E3 can be divided into two subfamilies according to their different structure characters and function mechanisms,the HECT(homologous to E6AP C terminus) family and the RING-finger family.Members of the HECT E3 share the common HECT catalytic domain,which can bind to an E2 and load the ubiquitin on themselves before catalyzing the transfer of ubiquitin to the target proteins.While the RING-finger E3 all contain an similar E2 binding domain and a unique substrate binding part,mediating direct ubiquitin transfer from the E2 to the substrate.The most recent progresses in the stuctural and functional studies of these two E3 famlies were summarized.