Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model

eLife, Journal Year: 2022, Volume and Issue: 11

Published: June 28, 2022

Mutations in the RNA helicase, DDX3X , are a leading cause of Intellectual Disability and present as syndrome, neurodevelopmental disorder associated with cortical malformations autism. Yet, cellular molecular mechanisms by which controls development largely unknown. Here, using mouse model Ddx3x loss-of-function we demonstrate that directs translational cell cycle control neural progenitors, underlies precise corticogenesis. First, show brain is sensitive to dosage; complete loss from progenitors causes microcephaly females, whereas hemizygous males heterozygous females reduced neurogenesis without marked microcephaly. In addition, sexually dimorphic, its paralog, Ddx3y compensates for developing male neocortex. Using live imaging promotes neuronal generation regulating both duration neurogenic divisions. Finally, use ribosome profiling vivo discover repertoire translated transcripts including those DDX3X-dependent essential neurogenesis. Our study reveals invaluable new insights into etiology implicating dysregulated progenitor dynamics translation pathogenic mechanisms.

Language: Английский

---

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(9), P. 6390 - 6418

Published: April 29, 2022

Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure–activity relationships, efficacy performances of these selective nonselective CDK inhibitors. The theoretical basis early broad-spectrum is similar to scope chemotherapy, but because toxicity greater benefit, there no window. notion a safer potential pan-CDK has widely recognized during research process. Four CDK4/6 for treatment breast cancer prophylactic administration chemotherapy protect bone marrow immune system function. Furthermore, emerging strategies field are summarized briefly, CDKs continue be pursued as anticancer drug targets discovery.

Language: Английский

---

PolyQ-expanded ataxin-2 aggregation impairs cellular processing-body homeostasis via sequestering the RNA helicase DDX6

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(7), P. 107413 - 107413

Published: May 27, 2024

Ataxin-2 (Atx2) is a polyglutamine (polyQ) tract-containing RNA-binding protein, while its polyQ expansion may cause protein aggregation that implicated in the pathogenesis of neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2). However, molecular mechanism underlying how Atx2 contributes to proteinopathies remains elusive. Here, we investigated influence on assembly and functionality cellular processing bodies (P-bodies) by using biochemical fluorescence imaging approaches. We have revealed polyQ-expanded (PQE) sequesters DEAD-box RNA helicase (DDX6), an essential component P-bodies, into aggregates or puncta via some sequences. The N-terminal like-Sm (LSm) domain (residues 82-184) C-terminal DDX6 are responsible for interaction specific sequestration. Moreover, sequestration aggravate pre-mRNA mis-splicing, interfere with releasing endoribonuclease MARF1 promotes mRNA decay translational repression. Rescuing level can recover P-bodies preventing targeted from degradation. This study provides line evidence P-body components impairment homeostasis dysregulating metabolism, which disease pathologies potential therapeutic target.

Language: Английский

---

Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Aug. 19, 2023

Abstract There is increasing evidence indicating the significant role of DDX5 (also called p68), acting as a master regulator and potential biomarker target, in tumorigenesis, proliferation, metastasis treatment resistance for cancer therapy. However, has also been reported to act an oncosuppressor. These seemingly contradictory observations can be reconciled by DDX5’s DNA repair. This because cell apoptosis malignant transformation represent two possible outcomes single process regulated DDX5, reflecting different intensity damage. Thus, targeting could potentially shift cells from growth-arrested state (necessary repair) killing. In addition increasingly recognized global genome stability surveillance damage repair, implicated multiple oncogenic signaling pathways. appears utilize distinct cascades via interactions with unique proteins types tissues/cells elicit opposing roles (e.g., smooth muscle versus cells). Such features make intriguing therapeutic target human cancers, limited low toxicity normal tissues. this review, we discuss multifaceted functions repair cancer, immune suppression, metabolic rewiring, virus infection promotion, negative impact on microbiome (microbiota). We provide new data showing that FL118, molecular glue degrader, selectively works against current treatment-resistant prostate organoids/cells. Altogether, studies demonstrate may oncotarget effectively conquering minimal

Language: Английский

---

Emerging Implications of Phase Separation in Cancer

Advanced Science, Journal Year: 2022, Volume and Issue: 9(31)

Published: Sept. 18, 2022

Abstract In eukaryotic cells, biological activities are executed in distinct cellular compartments or organelles. Canonical organelles with membrane‐bound structures well understood. Cells also inherently contain versatile membrane‐less (MLOs) that feature liquid gel‐like bodies. A biophysical process termed liquid–liquid phase separation (LLPS) elucidates how MLOs form through dynamic biomolecule assembly. LLPS‐related molecules often have multivalency, which is essential for low‐affinity inter‐ intra‐molecule interactions to trigger separation. Accumulating evidence shows LLPS concentrates and organizes desired segregates unneeded cells. Thus, tunable functional specificity response environmental stimuli metabolic processes. Aberrant widely associated several hallmarks of cancer, including sustained proliferative signaling, growth suppressor evasion, cell death resistance, telomere maintenance, DNA damage repair, etc. Insights into the molecular mechanisms provide new insights cancer therapeutics. Here, current understanding emerging concepts its involvement comprehensively reviewed.

Language: Английский

---

DEAD/H-Box Helicases in Immunity, Inflammation, Cell Differentiation, and Cell Death and Disease

Cells, Journal Year: 2022, Volume and Issue: 11(10), P. 1608 - 1608

Published: May 11, 2022

DEAD/H-box proteins are the largest family of RNA helicases in mammalian genomes, and they present all kingdoms life. Since their discovery late 1980s, have been a major focus study. They found to play central roles metabolism, gene expression, signal transduction, programmed cell death, immune response bacterial viral infections. Aberrant functions implicated wide range human diseases that include cancer, neurodegeneration, inherited genetic disorders. In this review, we provide historical context discuss molecular proteins, highlighting recent discoveries linking dysregulation diseases. We will also state knowledge regarding two specific critical responses DDX3X DDX58, known as RIG-I. Given importance homeostasis disease, an improved understanding protein biology protein–protein interactions be for informing strategies counteract pathogenesis associated with several

Language: Английский

---

Recent Progress in CDK4/6 Inhibitors and PROTACs

Molecules, Journal Year: 2023, Volume and Issue: 28(24), P. 8060 - 8060

Published: Dec. 13, 2023

Cell division in eukaryotes is a highly regulated process that critical to the life of cell. Dysregulated cell proliferation, often driven by anomalies Cyclin-dependent kinase (CDK) activation, key pathological mechanism cancer. Recently, selective CDK4/6 inhibitors have shown clinical success, particularly treating advanced-stage estrogen receptor (ER)-positive and human epidermal growth factor 2 (HER2)-negative breast This review provides an in-depth analysis action recent advancements inhibitors, categorizing them based on their structural characteristics origins. Furthermore, it explores proteolysis targeting chimers (PROTACs) CDK4/6. We hope this could be benefit for further research PROTACs.

Language: Английский

---

Cell growth and the cell cycle: New insights about persistent questions

BioEssays, Journal Year: 2022, Volume and Issue: 44(11)

Published: Oct. 12, 2022

Abstract Before a cell divides into two daughter cells, it typically doubles not only its DNA, but also mass. Numerous studies in cells ranging from yeast to mammals have shown that cellular growth, stimulated by nutrients and/or growth factor signaling, is prerequisite for cycle progression most types of cells. The textbook view growth‐regulated cycles signaling activates the transcription G1 Cyclin genes induce proliferation, and stimulates anabolic metabolism parallel. However, genetic knockout tests model organisms indicate this whole story, new show additional, “smarter” mechanisms help coordinate with itself. Here we summarize recent advances field, discuss current models which regulates proliferation targeting core regulators via non‐transcriptional mechanisms.

Language: Английский

---

DDX21 Controls Cell Cycle Progression and Autophagy in Pancreatic Cancer Cells

Cancers, Journal Year: 2025, Volume and Issue: 17(4), P. 570 - 570

Published: Feb. 7, 2025

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer. Late diagnosis and acquisition of chemoresistance contribute to its dismal prognosis. While surgical resection improved the clinical outcome patients, only ~20% them are eligible due advanced disease at diagnosis. Thus, development new therapeutic approaches master priority for an management this The helicase DDX21 was proposed as prognostic marker in several tumors, including PDAC. Methods:DDX21 expression evaluated PDAC samples cell lines; RNA sequencing bioinformatics analyses DDX21-depleted PANC-1 silenced cells; functional autophagy, cycle proliferation. Results: expressed higher levels liver metastasis patients. Transcriptomics cells revealed enrichment genes involved autophagy progression. inactivation by interference enhanced basal autophagic flux altered reducing rate G1-S transition. Coherently, proliferation clonogenic activity significantly reduced. Conclusions: Our results support oncogenic role uncover regulation autophagy.

Language: Английский

---

Unravelling the role of Interleukin-12 in Neuroinflammatory mechanisms: Pathogenic pathways linking Neuroinflammation to neuropsychiatric disorders

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 156, P. 114654 - 114654

Published: April 27, 2025

Language: Английский

---