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DNA-damage orchestrates self-renewal and differentiation via reciprocal p53 family and Hippo/Wnt/TGF-β pathway activation in embryonic stem cells.
Cell Mol Life Sci
January 2025
Cam-Su Genomic Resource Center, Medical College of Soochow University, Suzhou, China.
The mechanism by which DNA-damage affects self-renewal and pluripotency remains unclear. DNA damage and repair mechanisms have been largely elucidated in mutated cancer cells or simple eukaryotes, making valid interpretations on early development difficult. Here we show the impact of ionizing irradiation on the maintenance and early differentiation of mouse embryonic stem cells (ESCs).
View Article and Find Full Text PDFLethal clinical outcome and chemotherapy and immunotherapy resistance in patients with urothelial carcinoma with MDM2 amplification or overexpression.
J Immunother Cancer
January 2025
NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Background: The E3 ubiquitin ligase murine double minute 2 (MDM2) binds the p53 transcriptional activation domain and acts as a potent inhibitor of pathway, one of the three most crucial oncogenic pathways in urothelial carcinoma (UC). However, the clinical significance and impact on tumor immune contexture of amplification in UC remain unclear.
Methods: This study analyzed 240 patients with UC with matched clinical annotations from two local cohorts (ZSHS cohort and FUSCC cohort).
Inhibition of proteolytic and ATPase activities of the proteasome by the BTK inhibitor CGI-1746.
iScience
November 2024
Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 720 S. Donahue Dr., Auburn, AL, USA.
Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, has been shown to synergize with proteasome inhibitors (PIs) in reducing the viability of cells derived from B cell malignancies, but the mechanism is not known. We report here that an off-target effect of ibrutinib causes synergy because not all BTK inhibitors exhibited the synergistic effect, and those that synergized did so even in cells that do not express BTK. The allosteric BTK inhibitor CGI-1746 showed the strongest synergy.
View Article and Find Full Text PDFSystematic and comprehensive insights into HIF-1 stabilization under normoxic conditions: implications for cellular adaptation and therapeutic strategies in cancer.
Cell Mol Biol Lett
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School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
Hypoxia-inducible factors (HIFs) are essential transcription factors that orchestrate cellular responses to oxygen deprivation. HIF-1α, as an unstable subunit of HIF-1, is usually hydroxylated by prolyl hydroxylase domain enzymes under normoxic conditions, leading to ubiquitination and proteasomal degradation, thereby keeping low levels. Instead of hypoxia, sometimes even in normoxia, HIF-1α translocates into the nucleus, dimerizes with HIF-1β to generate HIF-1, and then activates genes involved in adaptive responses such as angiogenesis, metabolic reprogramming, and cellular survival, which presents new challenges and insights into its role in cellular processes.
View Article and Find Full Text PDFFLT3 Inhibitors Induce p53 Instability, Driven by STAT5/MDM2/p53 Competitive Interactions in Acute Myeloid Leukemia.
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Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China. Electronic address:
FLT3 mutations are present in one third of patients with Acute myeloid leukemia (AML) and stand as an attractive therapeutic target. Although FLT3 inhibitors demonstrate clinical efficacy, the drug resistance remains challenging attributed to multiple mechanisms. In this study, we found that tyrosine kinase inhibitors (TKIs) targeting FLT3 prompt p53 degradation in AML cells with FLT3-ITD through ubiquitination.
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