Objective: To evaluate the role of oncogene mdm2 and p53 in the development of orbital rhabdomyosarcoma (ORMS) and demonstrate the feasibility of mdm2 and p53 as biological characteristic markers and prognostic indicators.
Methods: Immunostainings of mdm2, p53 and Ki-67 antigen were performed on archival paraffin-embedded tissues taken from 31 ORMS patients. In situ hybridization was used to demonstrate the expression of mdm2 and p53 on the mRNA level. The correlations between the two genes and the clinical histopathologic parameters including age, gender, cells subtype, differentiation grade and proliferation index were analyzed.
Results: The positive expressions of mdm2 and p53 were 77.4% (24/31) and 71.0% (22/31) respectively; and the co-expression of mdm2 and p53 was 61.3%. The expressions of mdm2 and p53 on the protein level were in coincidence with that on the mRNA level. (1)The poorly and moderately differentiated group showed significantly higher expression of mdm2 and co-expression of mdm2-p53 than the well-differentiated group (P = 0.007; P = 0.009, respectively). (2) The samples were divided into actively-proliferating group and inactively-proliferating group in accordance with the expression of Ki-67 protein. The positive expression of p53 was significantly higher in actively-proliferating group than inactively-proliferating group. No statistic correlation of the positive expression of mdm2 and p53 with the other histopathologic parameters was observed.
Conclusions: mdm2 and p53 were significantly correlated with the differentiation and proliferation of ORMS. The co-expression of mdm2 and p53 expression suggested that mdm2 might play a role in deactivation of p53. The overexpression of mdm2 and p53 leaded to the loss of cell cycle control and may contribute to the tumorigenesis and tumor progression of ORMS. Mdm2 and p53 may be prognostic indicators of the tumor.
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Blood
January 2025
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
Stemness-associated cell states are linked to chemotherapy resistance in AML. We uncovered a direct mechanistic link between expression of the stem cell transcription factor GATA2 and drug resistance. The GATA-binding protein 2 (GATA2) plays a central role in blood stem cell generation and maintenance.
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Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), Universidad de Zaragoza, Zaragoza, Spain.
PADI4 is one of the human isoforms of a family of enzymes involved in the conversion of arginine to citrulline. MDM2 is an E3 ubiquitin ligase that is critical for degradation of the tumor suppressor gene p53. We have previously shown that there is an interaction between MDM2 and PADI4 in cellulo, and that such interaction occurs through the N-terminal region of MDM2, N-MDM2, and in particular through residues Thr26, Val28, Phe91, and Lys98.
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January 2025
School of Chemistry, Advanced Research Centre, University of Glasgow 11 Chapel Lane Glasgow G11 6EW UK
Peptide stapling is an effective strategy to stabilise α-helical peptides, enhancing their bioactive conformation and improving physiochemical properties. In this study, we apply our novel diyne-girder stapling approach to the MDM2/MDMX α-helical binding region of the p53 transactivation domain. By incorporation of an unnatural amino acid to create an optimal , + 7 bridge length, we developed a highly α-helical stapled peptide, 4, confirmed circular dichroism.
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January 2025
International Joint Research Laboratory for Perception Data Intelligent Processing of Henan, Anyang Normal University, Anyang, 455000, China.
Deconvoluting drug targets is crucial in modern drug development, yet both traditional and artificial intelligence (AI)-driven methods face challenges in terms of completeness, accuracy, and efficiency. Identifying drug targets, especially within complex systems such as the p53 pathway, remains a formidable task. The regulation of this pathway by myriad stress signals and regulatory elements adds layers of complexity to the discovery of effective p53 pathway activators.
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D3 Drug Tech Lab Pvt Ltd, Chennai, Tamilnadu, India.
Lung cancer is the leading cause of mortality in both men and women due to genetic and epigenetic modifications. Our study focuses on fabricating phenmiazine ring leads by a functional group-based drug design to inhibit p53 -7A1W and MDM2-7AU9 proteins responsible for cancer cell growth. One hundred molecules are designed and allowed to bind inside the active site of 7A1W and 7AU9 protein using a glide dock platform and subjected to find MMGBSA.
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