An image-based screen for secreted proteins involved in breast cancer G0 cell cycle arrest DOI Creative Commons
William Weston,

Jordan A. Holt,

Anna J. Wiecek

et al.

Scientific Data, Journal Year: 2024, Volume and Issue: 11(1)

Published: Aug. 10, 2024

Secreted proteins regulate the balance between cellular proliferation and G0 arrest therefore play important roles in tumour dormancy. Tumour dormancy presents a significant clinical challenge for breast cancer patients, where non-proliferating, G0-arrested cells remain at metastatic sites, below level of detection, some which can re-enter drive relapse. Knowing secreted entry into exit from allows us to manipulate their signalling prevent To identify novel that promote arrest, we performed secretome-wide, image-based screen increase fraction arrest. From secretome library 1282 purified proteins, identified 29 candidates non-transformed transformed epithelial cells. The assay have developed be adapted use other perturbation screens cell types. All datasets been made available re-analysis our candidate are presented alternative bioinformatic refinement or further experimental follow up.

Language: Английский

The ribotoxic stress response drives UV-mediated cell death DOI Creative Commons
Niladri K. Sinha, Connor McKenney,

Zhong Y. Yeow

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(14), P. 3652 - 3670.e40

Published: June 5, 2024

While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also RNA, triggering transcriptome-wide ribosomal collisions and a ribotoxic stress (RSR). However, relative contributions, timing, regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, biochemical approaches to create chronological atlas signaling events activated cells responding UV damage. We discover that UV-induced apoptosis mediated by RSR kinase ZAK not through DDR. identify two negative-feedback modules regulate ZAK-mediated apoptosis: (1) GCN2 activation limits attenuates (2) activity leads phosphodegron autophosphorylation its subsequent degradation. These tune ZAK's collision levels establish regimes homeostasis, tolerance, death, revealing key role as cellular sentinel for nucleic acid

Language: Английский

Citations

27
Cellular responses to RNA damage DOI Creative Commons
Jacqueline Cordes,

Shubo Zhao,

Christoph Engel

et al.

Cell, Journal Year: 2025, Volume and Issue: 188(4), P. 885 - 900

Published: Feb. 1, 2025

RNA plays a central role in protein biosynthesis and performs diverse regulatory catalytic functions, making it essential for all processes of life. Like DNA, is constantly subjected to damage from endogenous environmental sources. However, while the DNA response has been extensively studied, was long assumed that lesions are relatively inconsequential due transient nature most molecules. Here, we review recent studies challenge this view by revealing complex responses determine survival when cells exposed nucleic acid-damaging agents promote resolution lesions.

Language: Английский

Citations

2
Interactions between lncRNAs and cyclins/CDKs complexes; key players in determining cancer cell response to CDKs inhibitors DOI

Bahaa Ibrahim Saeed,

Abhinav Kumar, Enwa Felix Oghenemaro

et al.

Experimental Cell Research, Journal Year: 2025, Volume and Issue: 445(2), P. 114406 - 114406

Published: Jan. 4, 2025

Language: Английский

Citations

0
Tetraploidy in normal tissues and diseases: mechanisms and consequences DOI Creative Commons

Micheline Kirsch‐Volders,

Miroslav Mišík, Michael Fenech

et al.

Chromosoma, Journal Year: 2025, Volume and Issue: 134(1)

Published: March 21, 2025

Abstract Tetraploidisation plays a crucial role in evolution, development, stress adaptation, and disease, but its beneficial or pathological effects different tissues remain unclear. This study aims to compare physiological unphysiological tetraploidy eight steps: 1) mechanisms of diploidy-to-tetraploidy transition, 2) induction elimination tetraploidy, 3) tetraploid cell characteristics, 4) stress-induced 5) comparison vs. 6) consequences 7) nutritional pharmacological prevention strategies tetraploidisation, 8) knowledge gaps future perspectives. Unphysiological is an adaptive response at given threshold, often involving mitotic slippage. If cells evade through apoptosis immune surveillance, they may re-enter the cycle, causing genetic instability, micronuclei formation, aneuploidy, modification epigenome development diseases. The potential contributions neurodegenerative, cardiovascular diabetes related diseases are summarized schematic figures contrasted with cancer development. responsible for transition from tolerance tetraploidisation not fully understood. Understanding these critical importance allow targeted therapies.

Language: Английский

Citations

0
Cell cycle regulation by the ribotoxic stress response DOI
Connor McKenney, Sergi Regot

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

Citations

0
Binding Modalities and Phase-Specific Regulation of Cyclin/Cyclin-Dependent Kinase Complexes in the Cell Cycle DOI
Michael T. Bergman, Wengang Zhang, Yonglan Liu

et al.

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 24, 2024

Cyclin-dependent kinases (CDKs) are activated upon cyclin-binding to enable progression through the cell cycle. Dominant CDKs and cyclins in mammalian cells include CDK1, CDK2, CDK4, CDK6 corresponding A, B, D, E. While only certain, "typical" cyclin/CDK complexes primarily responsible for cycle progression, "atypical" can form sometimes perform same roles as typical complexes. We asked what structural features of favor formation complexes, a vital yet not fully explored question. use computational docking biophysical analyses exhaustively evaluate structure stability all CDK cyclin listed above. find that binding is generally stronger than atypical especially when an active conformation. Typical have denser clusters, indicating they more defined sites Our results help explain three notable function cycle: (i) why CDK4 cyclin-D exceptionally high specificity each other; (ii) both cyclin-A cyclin-B strongly activate whereas CDK2 by cyclin-A; (iii) cyclin-E normally activates but CDK1. Overall, this work reveals modalities how lead preference versus differ between observations suggest targeting catalytic actions destabilizing their native differential interfaces.

Language: Английский

Citations

3
Sanguinarine identified as a natural dual inhibitor of AURKA and CDK2 through network pharmacology and bioinformatics approaches DOI Creative Commons
Xiang Li, Qi You

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 28, 2024

Cervical cancer (CA) continues to be a female malignant tumor with limited therapeutic options, resulting in high mortality rate. Sanguinarine (SANG), naturally occurring alkaloid, has demonstrated notable efficacy preclinical treatment of CA. However, the mechanism through which SANG acts against CA is not fully understood. To address this, utilizing nine drug target prediction databases, we have successfully identified 379 potential targets for SANG. Venn diagram analysis compared 2367 CA-related from GeneCards disease database, 2618 CA-closely related derived multiple datasets GEO WGCNA analysis, and SANG, 35 shared targets. Subsequently, by employing PPI network Cytohubba plugin, Human Protein Atlas, TCGA database data, ROC curve AURKA CDK2 as key combating Single-gene GSEA results suggest that overexpression closely correlated DNA replication, cell cycle progression, various repair pathways Molecular docking molecular simulation dynamics analyses confirmed stable binding both In summary, integrating diverse methodological approaches, this study discovered potentially inhibits features targeting CDK2, thereby regulating pathways. This lays solid foundation further exploring pharmacological role therapy. in-depth vitro vivo experiments are required corroborate our findings.

Language: Английский

Citations

1
A reverse brake for the cell cycle DOI
Bart Westendorp

Science, Journal Year: 2024, Volume and Issue: 384(6695), P. 512 - 513

Published: May 2, 2024

Mitogenic signaling acts beyond S-phase entry to prevent whole-genome duplications

Language: Английский

Citations

0
An image-based screen for secreted proteins involved in breast cancer G0 cell cycle arrest DOI Creative Commons
William Weston,

Jordan A. Holt,

Anna J. Wiecek

et al.

Scientific Data, Journal Year: 2024, Volume and Issue: 11(1)

Published: Aug. 10, 2024

Secreted proteins regulate the balance between cellular proliferation and G0 arrest therefore play important roles in tumour dormancy. Tumour dormancy presents a significant clinical challenge for breast cancer patients, where non-proliferating, G0-arrested cells remain at metastatic sites, below level of detection, some which can re-enter drive relapse. Knowing secreted entry into exit from allows us to manipulate their signalling prevent To identify novel that promote arrest, we performed secretome-wide, image-based screen increase fraction arrest. From secretome library 1282 purified proteins, identified 29 candidates non-transformed transformed epithelial cells. The assay have developed be adapted use other perturbation screens cell types. All datasets been made available re-analysis our candidate are presented alternative bioinformatic refinement or further experimental follow up.

Language: Английский

Citations

0