Real-Time Measurement of a Weak Interaction of a Transcription Factor Motif with a Protein Hub at Single-Molecule Precision DOI Creative Commons
Lauren A. Mayse, Yazheng Wang, Mohammad Ahmad

и другие.

ACS Nano, Год журнала: 2024, Номер 18(31), С. 20468 - 20481

Опубликована: Июль 25, 2024

Transcription factors often interact with other protein cofactors, regulating gene expression. Direct detection of these brief events using existing technologies remains challenging due to their transient nature. In addition, intrinsically disordered domains, intranuclear location, and lack cofactor-dependent active sites transcription further complicate the quantitative analysis critical processes. Here, we create a genetically encoded label-free sensor identify interaction between motif MYC factor, primary cancer driver, WDR5, chromatin-associated hub. Using an engineered nanopore equipped this motif, WDR5 is probed through reversible captures releases in one-by-one time-resolved fashion. Our single-molecule kinetic measurements indicate weak-affinity arising from relatively slow complex association fast dissociation tethered motif. Further, validate subtle by determinations ensemble single nanodisc-wrapped nanopores immobilized on biolayer interferometry sensor. This study also provides proof-of-concept for that reveals unique recognition signatures different binding sites. foundational work may be developed produce sensing elements analytical proteomics nanomedicine.

Язык: Английский

Deubiquitinases in cancer DOI
Grant Dewson, Pieter J.A. Eichhorn, David Komander

и другие.

Nature reviews. Cancer, Год журнала: 2023, Номер 23(12), С. 842 - 862

Опубликована: Ноя. 7, 2023

Язык: Английский

Процитировано

124
Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers DOI
Jeffrey A. Klomp, Jennifer E. Klomp, Clint A. Stalnecker

и другие.

Science, Год журнала: 2024, Номер 384(6700)

Опубликована: Июнь 6, 2024

How the

Язык: Английский

Процитировано

37
Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity DOI Creative Commons
Brian Ortmann

BMJ Oncology, Год журнала: 2024, Номер 3(1), С. e000154 - e000154

Опубликована: Фев. 1, 2024

Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge cancer treatment is tumour microenvironment particular hypoxia (low oxygen levels), contributes progression immune evasion. At cellular level, this primarily governed by hypoxia-inducible factor (HIF). HIF a transcription that orchestrates responses low levels, driving angiogenesis, metabolic adaptation regulation. HIF's dysregulation frequently observed various types correlates with increased aggressiveness, metastasis, resistance therapy poor patient prognosis. Consequently, understanding mechanisms underlying activation downstream effects has become crucial developing targeted therapies for improving outcomes represents key step towards precision medicine. Recent advancements drug development have led emergence inhibitors, aim disrupt HIF-driven processes providing benefit. Here, we provide review molecular through promotes growth resistance, emphasising potential clinical benefits HIF-targeted therapies. This will discuss opportunities associated translating inhibition into practice, including ongoing trials future directions HIF-based treatments.

Язык: Английский

Процитировано

26
MYC function and regulation in physiological perspective DOI Creative Commons
Rajeev Jha, Fedor Kouzine, David Levens

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Окт. 24, 2023

MYC, a key member of the Myc-proto-oncogene family, is universal transcription amplifier that regulates almost every physiological process in cell including cycle, proliferation, metabolism, differentiation, and apoptosis. MYC interacts with several cofactors, chromatin modifiers, regulators to direct gene expression. levels are tightly regulated, deregulation has been associated numerous diseases cancer. Understanding comprehensive biology under conditions an utmost necessity demark biological functions from its pathological functions. Here we review recent advances mechanisms, functions, regulation MYC. We also emphasize role as global amplifier.

Язык: Английский

Процитировано

34
Targeting MYC at the intersection between cancer metabolism and oncoimmunology DOI Creative Commons
Simran Venkatraman, Brinda Balasubramanian, Chanitra Thuwajit

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Фев. 8, 2024

MYC activation is a known hallmark of cancer as it governs the gene targets involved in various facets progression. Of interest, oncometabolism through interactions with its partners and cofactors, well immunity via targets. Recent investigations have taken interest characterizing these multi-Omic approaches, to better understand vastness network. several either or oncoimmunology, few them overlap function. Prominent been observed HIF-1α, promoting glucose glutamine metabolism antigen presentation on regulatory T cells, subsequent metabolic reprogramming. This review explores existing knowledge role oncoimmunology. It also unravels how transcription influences cellular facilitate induction pro- anti-tumoral immunity. Moreover, considering significant roles holds development, present study discusses effective direct indirect therapeutic strategies combat MYC-driven

Язык: Английский

Процитировано

13
Targeting both the enzymatic and non-enzymatic functions of DHODH as a therapeutic vulnerability in c-Myc-driven cancer DOI Creative Commons
Qiang Zhang, Kaisa Cui,

Yue Kong

и другие.

Cell Reports, Год журнала: 2025, Номер 44(3), С. 115327 - 115327

Опубликована: Фев. 19, 2025

Язык: Английский

Процитировано

2
Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers DOI Creative Commons
David B. Freeman,

Tamara D. Hopkins,

Peter Mikochik

и другие.

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(23), С. 15629 - 15647

Опубликована: Ноя. 15, 2023

Transcriptional deregulation is a hallmark of many cancers and exemplified by genomic amplifications the MYC family oncogenes, which occur in at least 20% all solid tumors adults. Targeting transcriptional cofactors cyclin-dependent kinase (CDK9) has emerged as therapeutic strategy to interdict deregulated activity including oncogenic MYC. Here, we report structural optimization small molecule microarray hit, prioritizing maintenance CDK9 selectivity while improving on-target potency overall physicochemical pharmacokinetic (PK) properties. This led discovery potent, selective, orally bioavailable inhibitor 28 (KB-0742). Compound exhibits vivo antitumor mouse xenograft models projected human PK profile anticipated enable efficacious oral dosing. Notably, currently being investigated phase 1/2 dose escalation expansion clinical trial patients with relapsed or refractory tumors.

Язык: Английский

Процитировано

23
Strategies to target the cancer driver MYC in tumor cells DOI Creative Commons

Leonie I. Weber,

Markus Hartl

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Март 8, 2023

The MYC oncoprotein functions as a master regulator of cellular transcription and executes non-transcriptional tasks relevant to DNA replication cell cycle regulation, thereby interacting with multiple proteins. is required for fundamental processes triggering proliferation, growth, differentiation, or apoptosis also represents major cancer driver being aberrantly activated in most human tumors. Due its non-enzymatic biochemical largely unstructured surface, has remained difficult specific inhibitor compounds directly address, consequently, alternative approaches leading indirect inhibition have evolved. Nowadays, organic compounds, nucleic acids, peptides specifically interfering activities are preclinical early-stage clinical studies, but none them been approved so far the pharmacological treatment patients. In addition, efficient delivery technologies deliver MYC-inhibiting agents into MYC-dependent tumor cells just beginning emerge. this review, an overview direct their modes given. Furthermore, we summarize current possibilities appropriate drugs containing derailed using viral vectors nanoparticles. Finding right formulation target cancers achieve high intracellular concentration blocking attenuating oncogenic could be important development novel principles.

Язык: Английский

Процитировано

18
MYC—an emerging player in mitochondrial diseases DOI Creative Commons
Janne Purhonen, Juha Klefström, Jukka Kallijärvi

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Сен. 4, 2023

The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes the cell. In mitochondrial diseases, compromised respiratory electron transfer oxidative phosphorylation (OXPHOS) lead to compensatory rewiring with resemblance Warburg-like metabolic state cancer cells. transcription factor MYC (or c-MYC) regulator cancer, stimulating glycolysis, nucleotide biosynthesis, glutamine utilization, which are known predicted be affected also diseases. Albeit not widely acknowledged thus far, several cell mouse models disease show upregulation and/or its typical transcriptional signatures. Moreover, gene expression metabolite-level changes associated integrated stress response (mt-ISR) remarkable overlap those overexpression. addition being regulator, promotes proliferation modifies cycle kinetics and, especially at high levels, replication genomic instability, sensitizes cells apoptosis. Because requires energy doubling biomass, replicating should particularly sensitive defective OXPHOS. On other hand, OXPHOS-defective vulnerable levels as it facilitates evasion checkpoints accelerates progression. Indeed, few recent studies demonstrate defects nuclear DNA damage OXPHOS deficiency. Here, we give an overview key mitochondria-dependent pathways regulated by MYC, review current literature on speculate how may triggered deficiency what implications this has for pathogenesis these

Язык: Английский

Процитировано

18
Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure DOI
Munishwar N. Gupta, Vladimir N. Uversky

Protein Science, Год журнала: 2024, Номер 33(4)

Опубликована: Март 27, 2024

Abstract The rationale for replacing the old binary of structure–function with trinity structure, disorder, and function has gained considerable ground in recent years. A continuum model based on expanded form existing paradigm can now subsume importance both conformational flexibility intrinsic disorder protein function. is actually critical understanding protein–protein interactions many regulatory processes, formation membrane‐less organelles, our revised notions specificity as amply illustrated by moonlighting proteins. While its amyloids prions often discussed, roles infectious diseases under extreme conditions are also becoming clear. This review an attempt to discuss how current function, specificity, evolution fit better model. integration structure a single may bring greater clarity continuing quest proteins molecular mechanisms their functionality.

Язык: Английский

Процитировано

8