A5044896548- Phagocytosis and Immune Regulation
- Cell death mechanisms and regulation
- Immune cells in cancer
- Connexins and lens biology
- Skin and Cellular Biology Research
- TGF-β signaling in diseases
- Cell Adhesion Molecules Research
- DNA Repair Mechanisms
- Cancer-related Molecular Pathways
- Erythrocyte Function and Pathophysiology
- RNA regulation and disease
- Pancreatic function and diabetes
- Protein Kinase Regulation and GTPase Signaling
- Ferroptosis and cancer prognosis
- Pancreatic and Hepatic Oncology Research
- Occupational and environmental lung diseases
- Genomics and Chromatin Dynamics
- Molecular Biology Techniques and Applications
- Chromatin Remodeling and Cancer
- Neuroscience and Neuropharmacology Research
- RNA Research and Splicing
- Caveolin-1 and cellular processes
- Cardiac Fibrosis and Remodeling
- Genetic Mapping and Diversity in Plants and Animals
- Hedgehog Signaling Pathway Studies
Cancer Research UK Scotland Institute
2007-2024
Cancer Research UK
2015-2024
Switch
2022-2024
University of Glasgow
1995-2007
Beatson West of Scotland Cancer Centre
1996
CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that signaling is upregulated in human pancreatic cancer, predominantly neutrophil/myeloid-derived suppressor cells, but rarely tumor cells. Genetic ablation or inhibition of abrogated metastasis, only slowed tumorigenesis. Depletion neutrophils/myeloid-derived cells also suppressed metastasis suggesting a key role for establishing maintaining the metastatic niche. Importantly, loss improved...
Transforming growth factor-beta 1 (TGF-beta 1) is a modulator of cellular proliferation, differentiation, and extracellular matrix deposition. It potent epithelial inhibitor can alter the differentiative properties keratinocytes, in vitro, but little known about its normal physiological function epidermis vivo. Transgenic mice were generated using keratin 10 (K10) gene promoter to drive constitutive expression TGF-beta suprabasal keratinocyte compartment. Surprisingly, these showed two-...
To investigate the role of connexins in dominantly inherited skin disease, transgenic mice were produced which expressed mutant connexin 26 [gjb2/connexin 26(D66H)], from a keratin 10 promoter, exclusively suprabasal epidermis (the cells Connexin is up-regulated epidermal hyperproliferative states). From soon after birth, exhibited keratoderma similar to that humans carrying 26(D66H) mutation (true Vohwinkel syndrome). Transgene expression was associated with loss and 30 keratinocyte...
Barth syndrome is an X-linked mitochondrial disease, symptoms of which include neutropenia and cardiac myopathy. These are the most significant clinical consequences a increasingly recognised to have variable presentation. Mutation in Taz gene Xq28 thought be responsible for condition, by altering lipid content function. Male chimeras carrying targeted mutation on their X-chromosome were infertile. Testes from knockout smaller than control counterparts this was associated with disruption...
Pancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory proliferative capacity as well macropinocytosis. Macropinocytosis is understood nutrient scavenging mechanism, but little known about its functions trafficking signalling receptors. We find that CYRI-B highly expressed pancreatic mouse model p53-driven cancer. Deletion Cyrib (the...
Abstract ROCK kinases regulate actin‐myosin structures downstream of Rho GTPases. We generated mice expressing 4‐hydroxytamoxifen (4HT)‐regulated human II ( ROCKII:mER ™) under the transcriptional control cytokeratin14 K14 ) promoter. The K14‐ROCKII:mER ™ minigene was recombineered into a novel cloning vector containing promoter and first exon HPRT gene, second third exons mouse Hprt gene. Homologous recombination locus, which is deleted for two in HM1 embryonic stem cells, reconstitutes...
Apoptosis is characterized by profound morphological changes, but their physiological purpose unknown. To characterize the role of apoptotic cell contraction, ROCK1 was rendered caspase non-cleavable (ROCK1nc) mutating aspartate 1113, which revealed that cleavage necessary for forceful contraction and membrane blebbing. When homozygous ROCK1nc mice were treated with liver-selective stimulus diethylnitrosamine, had more liver damage greater neutrophil infiltration than wild-type mice....
Abstract The serine/threonine kinases ROCK1 and ROCK2 are central mediators of actomyosin contractile force generation that act downstream the RhoA small GTP‐binding protein. As a result, they have key roles in regulating cell morphology proliferation, been implicated numerous pathological conditions diseases including hypertension cancer. Here we describe gene‐targeted mouse line enables CRE‐inducible expression conditionally‐active fusion between kinase domain hormone‐binding mutated...
RNA polymerase III (Pol-III) transcribes tRNAs and other small RNAs essential for protein synthesis cell growth. Pol-III is deregulated during carcinogenesis; however, its role in vivo has not been studied. To address this issue, we manipulated levels of Brf1, a transcription factor that recruitment holoenzyme at tRNA genes vivo. Knockout Brf1 led to embryonic lethality blastocyst stage. In contrast, heterozygous mice were viable, fertile normal size. Conditional deletion gastrointestinal...
Abstract BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and elevated in numerous cancers. Here, we report that levels of associate with poor prognosis human prostate cancer. In vitro studies cancer cell lines demonstrated transient overexpression increased proliferation whereas the downregulation reduced mediated cycle arrest. Consistent our clinical observations, Pten -deficient mouse ( Δ/Δ Tg ) model accelerated carcinogenesis shortened survival. tumours,...
To elucidate the mode of action dominant mutant connexins in causing inherited skin diseases, transgenic mice were produced that express true Vohwinkel syndrome-associated Cx26 (D66H), from a keratin 10 promoter, specifically suprabasal epidermal keratinocytes. Following birth, developed keratoderma similar to human carriers (D66H). Expression transgene resulted loss and Cx30 at intercellular junctions keratinocytes accumulation these cytoplasm. Injection primary mouse with Lucifer Yellow...
Genetically encoded probes are widely used to visualize cellular processes in vitro and vivo. Although effective cultured cells, fluorescent protein tags reporters suboptimal vivo because of poor tissue penetration high background signal. Luciferase offer improved signal-to-noise ratios but require injections luciferin that can lead variable responses limit the number timing data points be gathered. Such issues studying critical transcription factor p53 have limited insight on its activity...
Abstract Increased protein synthesis supports growth of established tumours. However, how mRNA translation contributes to early tumorigenesis remains unclear. Here we show that following oncogene activation, hepatocytes enter a non-proliferative/senescent-like phase characterized by α5β1 integrin-dependent deposition fibronectin-rich extracellular matrix (ECM) niches. These niches then promote exit from oncogene-induced senescence permit progression proliferating hepatocellular carcinoma...
Abstract Increased protein synthesis drives proliferation of established tumours. However, how mRNA translation contributes to early tumorigenesis remains unclear. Following oncogene activation, hepatocytes enter a senescent phase characterized by deposition extracellular matrix (ECM) niches which promote subsequent progression hepatocellular carcinoma (HCC). We demonstrate an inverse relationship between rates and transition from this oncogene-induced state proliferating HCC. have found...