Ayala King

University of Glasgow, Glasgow, Scotland, United Kingdom

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Publications (9)61.2 Total impact

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    ABSTRACT: The acknowledgement that metabolic reprogramming is a central feature of cancer has generated high expectations for major advances in both diagnosis and treatment of malignancies through addressing metabolism. These have so far only been partially fulfilled, with only a few clinical applications. However, numerous diagnostic and therapeutic compounds are currently being evaluated in either clinical trials or pre-clinical models and new discoveries of alterations in metabolic genes indicate future prognostic or other applicable relevance. Altogether, these metabolic approaches now stand alongside other available measures providing hopes for the prospects of metabolomics in the clinic. Here we present a comprehensive overview of both ongoing and emerging clinical, pre-clinical and technical strategies for exploiting unique tumour metabolic traits, highlighting the current promises and anticipations of research in the field.
    Seminars in Cell and Developmental Biology 09/2015; DOI:10.1016/j.semcdb.2015.09.008 · 6.27 Impact Factor
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    ABSTRACT: Congenital melanocytic nevus (CMN) syndrome is the association of pigmented melanocytic nevi with extra-cutaneous features, classically melanotic cells within the CNS, most frequently caused by a mutation of NRAS codon 61. This condition is currently untreatable, and carries a significant risk of melanoma within the skin, brain or leptomeninges. We have previously proposed a key role for Wnt signaling in formation of melanocytic nevi, suggesting that activated Wnt signaling may be synergistic with activated NRAS in the pathogenesis of CMN syndrome. Some familial pre-disposition suggests a germ-line contribution to CMN syndrome, as does variability of neurological phenotypes in individuals with similar cutaneous phenotypes. Accordingly, we performed exome sequencing of germ-line DNA from patients with CMN to reveal rare or undescribed Wnt-signaling alterations. A murine model harboring activated NRAS(Q61K) and Wnt signaling in melanocytes exhibited striking features of CMN syndrome, in particular neurological involvement. In the first model of treatment for this condition, these congenital, and previously assumed permanent, features were profoundly suppressed by acute post-natal treatment with a MEK inhibitor. These data suggest that activated NRAS and aberrant Wnt signaling conspire to drive CMN syndrome. Post-natal MEK inhibition is a potential candidate therapy for patients with this debilitating condition.Journal of Investigative Dermatology accepted article preview online, 27 March 2015. doi:10.1038/jid.2015.114.
    Journal of Investigative Dermatology 03/2015; 135(8). DOI:10.1038/jid.2015.114 · 7.22 Impact Factor
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    ABSTRACT: Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.
    Nature Communications 01/2015; 6:6001. DOI:10.1038/ncomms7001 · 11.47 Impact Factor
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    ABSTRACT: Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Cellular senescence and associated tumor suppression depend on control of chromatin. Histone chaperone HIRA deposits variant histone H3.3 and histone H4 into chromatin in a DNA replication-independent manner. Appropriately for a DNA replication-independent chaperone, HIRA is involved in control of chromatin in nonproliferating senescent cells, although its role is poorly defined. Here, we show that nonproliferating senescent cells express and incorporate histone H3.3 and other canonical core histones into a dynamic chromatin landscape. Expression of canonical histones is linked to alternative mRNA splicing to eliminate signals that confer mRNA instability in nonproliferating cells. Deposition of newly synthesized histones H3.3 and H4 into chromatin of senescent cells depends on HIRA. HIRA and newly deposited H3.3 colocalize at promoters of expressed genes, partially redistributing between proliferating and senescent cells to parallel changes in expression. In senescent cells, but not proliferating cells, promoters of active genes are exceptionally enriched in H4K16ac, and HIRA is required for retention of H4K16ac. HIRA is also required for retention of H4K16ac in vivo and suppression of oncogene-induced neoplasia. These results show that HIRA controls a specialized, dynamic H4K16ac-decorated chromatin landscape in senescent cells and enforces tumor suppression. © 2014 Rai et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 12/2014; 28(24):2712-2725. DOI:10.1101/gad.247528.114 · 10.80 Impact Factor
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    ABSTRACT: Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescence-associated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescence-associated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.
    Proceedings of the National Academy of Sciences 09/2013; 110(40). DOI:10.1073/pnas.1303491110 · 9.67 Impact Factor
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    ABSTRACT: To generate and characterize a constitutively active, RPE-specific, cre-expressing transgenic mouse line. This line can be used to create RPE-specific knockouts by crossing with mice harboring loxP-flanked (floxed) genes. A transgene construct was assembled with the BEST1 promoter driving cre expression. Transgenic mice were generated on a C57BL/6 background. Cre expression was assessed by immunofluorescence and Western blot analysis. Cre enzymatic activity was tested by crossing to three lines with floxed DNA regions and detecting deletion of the intervening sequences or through histochemical detection of lacZ activity. Potential cre-mediated toxicity was assessed by retinal histology up to 24 months of age and by electroretinography. The BEST1-cre line with expression in the highest percentage of RPE cells displayed a patchy mosaic expression pattern, with 50% to 90% of RPE cells expressing cre. In mice outcrossed to a mixed B6/129 background, expression was consistently found in 90% of RPE cells. Within the eye, only the RPE cells were immunoreactive with an anti-cre antibody. Maximum cre expression quantified by Western blot analysis occurred at P28. Crosses with three lines containing floxed sequences revealed RPE-specific cre activity in the eye and extraocular expression limited to the testes. Histology and electroretinography showed no cre-mediated RPE toxicity. This BEST1-cre transgenic line enables generation of RPE-specific knockout mice. The mosaic expression pattern provides an internal control; the non-cre-expressing RPE cells continue to express the floxed genes. These mice should facilitate study of the multifunctional RPE and the generation of mouse models of human retinal disease.
    Investigative ophthalmology & visual science 03/2011; 52(3):1378-83. DOI:10.1167/iovs.10-6347 · 3.40 Impact Factor
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    Ayala King · Eyal Gottlieb
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    ABSTRACT: Over the last decade, cellular glucose metabolism has emerged as a central player in the mechanisms of programmed cell death (PCD). We examined the metabolic foundations of apoptosis from a Darwinian context and suggest that PCD has evolved from the cellular response to metabolic stress, most notably in relation to glucose metabolism. Whilst apoptosis and other forms of PCD are essential to the development, maintenance and survival of multicellular organisms, it is now evident that controlled and selective cell death confers fitness advantages in unicellular organisms. All species may thus harbour a fundamental relationship between the availability of basic nutrients and life/death decisions. This evolutionary perspective may inform our understanding of PCD in its many guises.
    Current opinion in cell biology 10/2009; 21(6):885-93. DOI:10.1016/j.ceb.2009.09.009 · 8.47 Impact Factor
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    ABSTRACT: Throughout the lifetime of an individual, light is focused onto the retina. The resulting photooxidative stress can cause acute or chronic retinal damage. The pathogenesis of age-related macular degeneration (AMD), the leading cause of legal blindness in the developed world, involves oxidative stress and death of the retinal pigment epithelium (RPE) followed by death of the overlying photoreceptors. Evidence suggests that damage due to exposure to light plays a role in AMD and other age-related eye diseases. In this work a system for light-induced damage and death of the RPE, based on the human ARPE-19 cell line, was used. Induction of mitochondria-derived reactive oxygen species (ROS) is shown to play a critical role in the death of cells exposed to short-wavelength blue light (425 +/- 20 nm). ROS and cell death are blocked either by inhibiting the mitochondrial electron transport chain or by mitochondria-specific antioxidants. These results show that mitochondria are an important source of toxic oxygen radicals in blue light-exposed RPE cells and may indicate new approaches for treating AMD using mitochondria-targeted antioxidants.
    Photochemistry and Photobiology 06/2004; 79(5):470-5. DOI:10.1562/LE-03-17.1 · 2.27 Impact Factor
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    ABSTRACT: To identify and characterize retinoblastoma protein (pRb) binding proteins that may influence retinoblast proliferation and retinal pigment epithelial cell survival. The yeast two-hybrid system was used to screen a bovine retinal cDNA library and to characterize positive clones. DNA sequencing and site-directed mutagenesis were used for further analysis. Co-immunoprecipitation experiments were used to confirm the results of the two-hybrid system in vivo. In the two-hybrid system, Protein Phosphatase 1alpha1 (PP1alpha1) binds the retinoblastoma protein. Unlike several other pRb binding proteins, PP1alpha1 binds only weakly to the Rb family member p107, and does not demonstrate detectable binding to p130. Confirming the two-hybrid results, endogenous PP1 in a human retinal pigment epithelial (RPE) cell line co-immunoprecipitates with endogenous pRb but not p107 or p130. Site directed mutagenesis of two pRb binding motifs in PP1alpha1 from LXSXE to LXCXE leads to slight increases in its two-hybrid interaction with pRb but does not alter its binding preference for pRb over the other family members. The complete sequence of bovine PP1alpha1 is reported. The strong two-hybrid interaction between PP1alpha1 and pRb, but not p107 or p130, suggests that the phosphorylation status of members of the pRb family may be regulated by different phosphatases, contributing to fine control of cell cycle progression. Conversely, PP1 activity may be specifically regulated by pRb and not p107 or p130. Mutagenesis studies suggest that PP1alpha1's LXSXE motif is not responsible for its binding preference for pRb over p107 and p130. Disruption of the PP1-pRb interaction may influence retinoblastoma tumorigenesis as well as RPE cell proliferation and survival.
    Current Eye Research 06/2002; 24(5):392-6. DOI:10.1076/ceyr.24.5.392.8524 · 1.64 Impact Factor

Publication Stats

161 Citations
61.20 Total Impact Points


  • 2015
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 2009–2014
    • Beatson Institute for Cancer Research
      Glasgow, Scotland, United Kingdom
  • 2011
    • University of Pennsylvania
      • Scheie Eye Institute
      Filadelfia, Pennsylvania, United States