A5038563523- Autophagy in Disease and Therapy
- Metabolism, Diabetes, and Cancer
- Computational Drug Discovery Methods
- Bioinformatics and Genomic Networks
- Pancreatic function and diabetes
- Calcium signaling and nucleotide metabolism
- Epigenetics and DNA Methylation
- Parkinson's Disease Mechanisms and Treatments
- FOXO transcription factor regulation
- Mitochondrial Function and Pathology
- Amino Acid Enzymes and Metabolism
- Alzheimer's disease research and treatments
- Cannabis and Cannabinoid Research
- Genetics, Bioinformatics, and Biomedical Research
- Histone Deacetylase Inhibitors Research
- Lysosomal Storage Disorders Research
- MicroRNA in disease regulation
- Mechanisms of cancer metastasis
- Advanced biosensing and bioanalysis techniques
- Telomeres, Telomerase, and Senescence
- Biomedical Text Mining and Ontologies
- Cancer, Hypoxia, and Metabolism
- PI3K/AKT/mTOR signaling in cancer
MRC Protein Phosphorylation and Ubiquitylation Unit
2018-2025
University of Dundee
2018-2025
AstraZeneca (United Kingdom)
2023-2025
Genomics (United Kingdom)
2023
Mutations in PINK1 and Parkin result autosomal recessive Parkinson's disease (PD). Cell culture vitro studies have elaborated the PINK1-dependent regulation of defined how this dyad orchestrates elimination damaged mitochondria via mitophagy. phosphorylates ubiquitin at serine 65 (Ser65) an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting activation; however, physiological significance phosphorylation vivo mammals remains unknown. To address this, we...
Mitophagy is a natural phenomenon and entails the lysosomal degradation of mitochondria by autophagy pathway. In recent years, development fluorescent pH-sensitive mitochondrial reporters has greatly facilitated monitoring mitophagy distinguishing between cytosolic or those delivered to acidic lysosomes. We recently published mito-QC reporter, which consists outer membrane-localised tandem mCherry-GFP tag. This allows quantification via increase in red-only mCherry signal that arises when...
Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether is a cause or consequence of such state changes. The signalling pathways that integrate to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated deferiprone, therapeutic iron chelator stimulates PINK1/PARKIN-independent mitophagy. Iron depletion profoundly rewired...
Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the receptors NIX BNIP3. Although AMP-activated protein kinase (AMPK), energy-sensing kinase, influence damaged-induced mitophagy, its role in is unclear. We found AMPK directly inhibits NIX-dependent by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 an additional...
Abstract Breast cancer is one of the most common cancers worldwide, and around 80% breast are oestrogen receptor positive (ER+ BC). For patients with ER+ advanced BC or more PIK3CA/AKT1/PTEN tumor alterations, capivasertib (AKT inhibitor) in combination fulvestrant (selective (ER) degrader) a recommended treatment. An innate PI3K/AKT pathway inhibitor resistance can occur BC, limiting their efficacy. Therefore, novel therapeutic strategies needed to increase sensitivity treatments BC. With...
Abstract Loss of PTEN expression, via homozygous or hemizygous deletion, is common in PIK3CA mutant ER + BC tumors. We assessed reduction protein expression on AKT inhibitor capivasertib efficacy altered In altered, high models, PI3Kα and inhibition was effective, however ablation partial attenuated PI3Kαi but not AKTi efficacy, alone combined with fulvestrant. Efficacy FOXO3 dependent associated FOXM1 downregulation. FOXO3A deletion reduced response to capivasertib, increased expression....
Abstract Combining fulvestrant (a selective estrogen receptor (ER) degrader) with the PI3K-AKT signalling inhibitors such as alpelisib (PI3Kα inhibitor) or capivasertib (AKT gives benefit to patients ER+ breast cancer (ER+ BC) harboring PIK3CA mutations (alpelisib) and PIK3CA, PTEN AKT-1 altered tumors (capivasertib). While are common, activation can also occur due other alterations, including in AKT-1, which alter pathway function dependency. Deletion of PTEN, leading ablation protein,...
Abstract Photoreceptor degeneration is the hallmark of retinitis pigmentosa. Identifying general mechanisms underlying photoreceptor cell death key to developing effective, mutation-independent treatments prevent vision loss. Mitophagy a protective pathway that prevents age-dependent loss and upregulated by iron chelators such as deferiprone (DFP). Therefore, we aimed investigate ability DFP protect against retinal via mitophagy. First, treated mitophagy reporter mice with MNU, classic...
Cellular senescence is believed to be a key driver of several age-related diseases, including COPD and IPF. Therefore, senothereapeutics represent an attractive area research with potential for future therapies against these debilitating diseases. To identify novel targets in unbiased manner, we set up arrayed whole genome CRISPR knock-out screen primary human lung fibroblasts (NHLFs) assessing etoposide-induced nuclear p21 expression as marker using confocal microscopy. The NHLF achieved...