Multitarget mechanism of MYC inhibition by the bacterial lon protease in disease

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 25, 2025

Abstract Identifying specific inhibitors of the MYC oncogene has been challenging, due to off target effects associated with inhibition. This study investigated how recombinant Escherichia coli Lon protease (rLon), which targets in human cells, inhibits over-activation models infection and cancer. In silico predictions identified peptide domains bacterial that affinity these peptides for was by surface plasmon resonance. The N-terminal domain rLon shown interact C-terminal, leucine zipper MAX prevent MYC/MAX dimerization. Furthermore, targeted degraded c-MYC vitro cellular models, through peptidase domain. a model kidney infection, treatment prevented, c-MYC, N-MYC L-MYC over-expression, MYC-dependent gene expression, specifically renal toxicity genes pathology, suggesting recognizes corrects dysregulation this disease. findings describe multitarget mechanism inhibition rLon, combined achieved domains, targeting different epitopes functions, no evidence or detrimental on homeostatic expression.

Language: Английский

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Myc and Tor drive growth and cell competition in the regeneration blastema ofDrosophilawing imaginal discs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 16, 2025

Abstract During the regeneration of injured or lost tissues, blastema serves as a hub for robust growth. Drosophila imaginal discs are genetically tractable and simple model system study organization this regrowth. Key signals that contribute to regenerative growth in these discs, such ROS, Wnt/Wg, JNK, p38, JAK/STAT, Hippo pathway, have been identified. However, detailed exploration spatial regrowth, factors directly drive growth, consequences activating drivers has not undertaken. Here, we find is controlled by transcription factor Myc Tor signaling, which additively proliferation translation blastema. The arranged into concentric zones defined expression, elevated activity, translation. In addition, increased expression innermost zone induced Xrp1-independent cell competition-like death adjacent zones, revealing delicate balance between driving inducing regenerating tissue. Summary statement wing disc characterized factor, signaling Myc-induced competition .

Language: Английский

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Novel Artificial 5′UTR Increase Modified mRNA Translation When Injected into Mouse Heart

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(4), P. 490 - 490

Published: April 8, 2025

Background/Objectives: Modified messenger RNA (modRNA) is a promising gene delivery method used to upregulate genes in cardiac tissue, with applications both clinical and preclinical settings prevent remodeling after ischemic injury. The 5′ untranslated region (5′UTR) plays crucial role regulating the translation efficiency of mRNA into functional proteins. Due high production cost short half-life modRNA, it essential identify novel 5′UTR designs that enhance modRNA heart. Methods: Here, we present an artificial 5′UTR, termed “Top Heart 5′UTR”, designed based on ribonucleotide frequency analyses 1000 highly expressed This contains unique 20-nucleotide sequence, consisting 11 previously uncharacterized nucleotides (CCCCCGCCCCC) 9 well-described from Kozak sequence upstream start codon (ATG). Results: design significantly improves cardiomyocytes (CMs) heart cells vitro vivo. Specifically, Top increases by approximately 30–60% mouse human CMs compared standard control. Moreover, induces 2–2.5 times higher 24 48 h post-delivery. Conclusions: Our findings may contribute development superior platform for use studies, potentially allowing reduced dosages or increased expression at same dosage level. approach can be extended optimized 5′UTRs various cell types organs, including cancer therapies.

Language: Английский

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A flexible, high-throughput system for studying mRNA translation kinetics in vitro and in cellulo with HiBit technology

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 27, 2024

Abstract HiBit is an engineered luciferase’s 11 amino acid component that can be introduced as a tag at either terminus of protein interest. When the LgBit and substrate are present, dimerise forming functional luciferase. The technology has been extensively used for high-throughput turnover studies in cells. Here, we have adapted use to quantify mRNA translation temporally vitro rabbit reticulocyte system cellulo HEK293 cells constitutively expressing LgBit. assay detect differences Cap, 5’UTR, modified nucleotide composition, coding sequence optimisation poly(A) length. Importantly, using these assays established optimal composition varied depending on encoded interest, highlighting importance screening methods tailored not reliant reporter proteins. Our findings demonstrated easily readily monitor offers novel highly favourable method development mRNA-based therapeutics. Graphical abstract

Language: Английский

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Role of Harmaline in Inhibiting c-Myc, Altering Molecular Typing, and Promoting Apoptosis in Triple-Negative Breast Cancer

Breast Cancer Targets and Therapy, Journal Year: 2024, Volume and Issue: Volume 16, P. 855 - 866

Published: Dec. 1, 2024

Objective: Triple-negative breast cancer (TNBC) lacks effective targeted, endocrine therapeutic agents and the development of novel is costly time-consuming. The objective this study was to identify pharmaceuticals natural products utilized in clinical practice that have potential inhibit expression Cellular-myelocytomatosis oncogene (c-Myc), based on a review current literature. aim assess effect specified drugs c-Myc TNBC cells, determine most potent inhibitor, evaluate its impact cell proliferation, invasive migration, apoptosis, as well estrogen receptor (ER), progesterone (PR), human epidermal growth factor 2 (HER-2) at both gene protein levels. Explore for treatment or adjuvant therapy triple-negative cancer. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) Western blot were used quantify Flow cytometry employed measure proliferation while Transwell assay invasion migration. Results: Harmaline emerged strongest significantly decreasing levels cells. It also inhibited invasion, migration promoting apoptosis Additionally, there varying increase ER PR genes proteins. While HER-2 elevated, no significant change Notably, phosphorylated increased. Conclusion: found promote cells by targeting inhibition c-Myc. induced re-expression ER, PR, genes, Keywords: c-Myc, harmaline, molecular typing,

Language: Английский

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