Effects of the p16/cyclin D1/CDK4/Rb/E2F1 pathway on aberrant lung fibroblast proliferation in neonatal rats exposed to hyperoxia

Chen, Zhongguang; Han, Shuang; Wu, Hongmin

doi:10.3892/etm.2021.10491

Cited by 2 publications

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer’s disease

Shin,

Kim,

Choi

et al. 2024

Mol Neurodegeneration

View full text Add to dashboard Cite

Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer’s disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle factor related to aging. We found that p16ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16ink4a in microglia is a promising strategy for the treatment of Alzheimer’s disease.

show abstract

Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer’s disease

Shin,

Kim,

Choi

et al. 2024

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

Regulation of Ferroptosis by Transcription Factor E2F1 and RB

Kuganesan

Dlamini

et al. 2023

Preprint

View full text Add to dashboard Cite

Tumor suppressor RB binds to E2F family proteins and modulates cell cycle progression. Cyclin dependent kinases (CDK) regulate the interaction of RB/E2F by phosphorylating RB. Previously, we have revealed that CDK2, RB and E2F inhibit ferroptosis. Ferroptosis is a non-apoptotic, iron-dependent form of cell death characterized by toxic lipid peroxidation. Here we provide evidence that CDK2 suppresses ferroptosis through phosphorylation of RB. We approach this question by overexpressing WT-RB or a mutant RB that cannot be phosphorylated by CDKs (RBΔCDK) along with CDK2/cyclinE followed by analysis of ferroptosis. We also observed that E2F1 regulates of both pro and anti-ferroptotic proteins including ALOX5, MYC SLC7A11, ATF4, and GPX4 and finally renders a net inhibitory role in ferroptosis. Interestingly, we also found a cell type dependent compensatory effect of E2F3 upon E2F1 depletion. This compensatory effect resulted in no change of ferroptotic target genes after E2F1 knock down in an osteosarcoma cell line. Taken together, our study reveals that cancer cells protect themselves from ferroptosis through cell cycle regulatory proteins.

show abstract

Effects of the p16/cyclin D1/CDK4/Rb/E2F1 pathway on aberrant lung fibroblast proliferation in neonatal rats exposed to hyperoxia

Cited by 2 publications

References 35 publications

Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer’s disease

Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer’s disease

Regulation of Ferroptosis by Transcription Factor E2F1 and RB

Contact Info

Product

Resources

About