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Lynsey Vaughan - One of the best experts on this subject based on the ideXlab platform.

  • huwe1 is a critical colonic tumour suppressor gene that prevents myc signalling dna damage accumulation and tumour initiation
    Embo Molecular Medicine, 2017
    Co-Authors: Kevin Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Alex Von Kriegsheim, Balazs Győrffy, Mamunur Rashid, Simona Polo, Elena Maspero, Lynsey Vaughan
    Abstract:

    Abstract Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1 , which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1 , we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc , with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc . The increased levels of DNA damage sensitised Huwe1 ‐deficient tumours to DNA‐damaging agents and to deletion of the anti‐apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a Potential Vulnerability of HUWE1 ‐mutated tumours to DNA‐damaging agents and inhibitors of anti‐apoptotic proteins.

  • huwe1 is a critical colonic tumour suppressor gene that prevents myc signalling dna damage accumulation and tumour initiation
    Embo Molecular Medicine, 2017
    Co-Authors: Kevin Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Balazs Győrffy, Mamunur Rashid, Simona Polo, Elena Maspero, Alex Von Kriegsheim, Lynsey Vaughan
    Abstract:

    Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc The increased levels of DNA damage sensitised Huwe1-deficient tumours to DNA-damaging agents and to deletion of the anti-apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a Potential Vulnerability of HUWE1-mutated tumours to DNA-damaging agents and inhibitors of anti-apoptotic proteins.

Charles R Tyler - One of the best experts on this subject based on the ideXlab platform.

  • expression dynamics of genes in the hypothalamic pituitary thyroid hpt cascade and their responses to 3 3 5 triiodo l thyronine t3 highlights Potential Vulnerability to thyroid disrupting chemicals in zebrafish danio rerio embryo larvae
    Aquatic Toxicology, 2020
    Co-Authors: Aoife Parsons, Anke Lange, Thomas H Hutchinson, Shinichi Miyagawa, Taisen Iguchi, Tetsuhiro Kudoh, Charles R Tyler
    Abstract:

    Some chemicals in the environment disrupt thyroid hormone (TH) systems leading to alterations in organism development, but their effect mechanisms are poorly understood. In fish, this has been limited by a lack of fundamental knowledge on thyroid gene ontogeny and tissue expression in early life stages. Here we established detailed expression profiles for a suite of genes in the hypothalamic-pituitary-thyroid (HPT) axis of zebrafish (Danio rerio) between 24-120 h post fertilisation (hpf) and quantified their responses following exposure to 3,3',5-triiodo-L-thyronine (T3) using whole mount in situ hybridisation (WISH) and qRT-PCR (using whole-body extracts). All of the selected genes in the HPT axis demonstrated dynamic transcript expression profiles across the developmental stages examined. The expression of thyroid receptor alpha (thraa) was observed in the brain, gastrointestinal tract, craniofacial tissues and pectoral fins, while thyroid receptor beta (thrb) expression occurred in the brain, otic vesicles, liver and lower jaw. The TH deiodinases (dio1, dio2 and dio3b) were expressed in the liver, pronephric ducts and brain and the patterns differed depending on life stage. Both dio1 and dio2 were also expressed in the intestinal bulb (96-120 hpf), and dio2 expression occurred also in the pituitary (48-120 hpf). Exposure of zebrafish embryo-larvae to T3 (30 and 100 μg L-1) for periods of 48, 96 or 120 hpf resulted in the up-regulation of thraa, thrb, dio3b, thyroid follicle synthesis proteins (pax8) and corticotropin-releasing hormone (crhb) and down-regulation of dio1, dio2, glucuronidation enzymes (ugt1ab) and thyroid stimulating hormone (tshb) (assessed via qRT-PCR) and responses differed across life stage and tissues. T3 induced thraa expression in the pineal gland, pectoral fins, brain, somites, gastrointestinal tract, craniofacial tissues, liver and pronephric ducts. T3 enhanced thrb expression in the brain, jaw cartilage and intestine, while thrb expression was suppressed in the liver. T3 exposure suppressed the transcript levels of dio1 and dio2 in the liver, brain, gastrointestinal tract and craniofacial tissues, while dio2 signalling was also suppressed in the pituitary gland. Dio3b expression was induced by T3 exposure in the jaw cartilage, pectoral fins and brain. The involvement of THs in the development of numerous body tissues and the responsiveness of these tissues to T3 in zebrafish highlights their Potential Vulnerability to exposure to environmental thyroid-disrupting chemicals.

Kevin Myant - One of the best experts on this subject based on the ideXlab platform.

  • huwe1 is a critical colonic tumour suppressor gene that prevents myc signalling dna damage accumulation and tumour initiation
    Embo Molecular Medicine, 2017
    Co-Authors: Kevin Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Alex Von Kriegsheim, Balazs Győrffy, Mamunur Rashid, Simona Polo, Elena Maspero, Lynsey Vaughan
    Abstract:

    Abstract Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1 , which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1 , we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc , with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc . The increased levels of DNA damage sensitised Huwe1 ‐deficient tumours to DNA‐damaging agents and to deletion of the anti‐apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a Potential Vulnerability of HUWE1 ‐mutated tumours to DNA‐damaging agents and inhibitors of anti‐apoptotic proteins.

  • huwe1 is a critical colonic tumour suppressor gene that prevents myc signalling dna damage accumulation and tumour initiation
    Embo Molecular Medicine, 2017
    Co-Authors: Kevin Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Balazs Győrffy, Mamunur Rashid, Simona Polo, Elena Maspero, Alex Von Kriegsheim, Lynsey Vaughan
    Abstract:

    Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc The increased levels of DNA damage sensitised Huwe1-deficient tumours to DNA-damaging agents and to deletion of the anti-apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a Potential Vulnerability of HUWE1-mutated tumours to DNA-damaging agents and inhibitors of anti-apoptotic proteins.

Michael C Hodder - One of the best experts on this subject based on the ideXlab platform.

  • huwe1 is a critical colonic tumour suppressor gene that prevents myc signalling dna damage accumulation and tumour initiation
    Embo Molecular Medicine, 2017
    Co-Authors: Kevin Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Alex Von Kriegsheim, Balazs Győrffy, Mamunur Rashid, Simona Polo, Elena Maspero, Lynsey Vaughan
    Abstract:

    Abstract Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1 , which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1 , we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc , with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc . The increased levels of DNA damage sensitised Huwe1 ‐deficient tumours to DNA‐damaging agents and to deletion of the anti‐apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a Potential Vulnerability of HUWE1 ‐mutated tumours to DNA‐damaging agents and inhibitors of anti‐apoptotic proteins.

  • huwe1 is a critical colonic tumour suppressor gene that prevents myc signalling dna damage accumulation and tumour initiation
    Embo Molecular Medicine, 2017
    Co-Authors: Kevin Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Balazs Győrffy, Mamunur Rashid, Simona Polo, Elena Maspero, Alex Von Kriegsheim, Lynsey Vaughan
    Abstract:

    Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc The increased levels of DNA damage sensitised Huwe1-deficient tumours to DNA-damaging agents and to deletion of the anti-apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a Potential Vulnerability of HUWE1-mutated tumours to DNA-damaging agents and inhibitors of anti-apoptotic proteins.

Patrizia Cammareri - One of the best experts on this subject based on the ideXlab platform.

  • huwe1 is a critical colonic tumour suppressor gene that prevents myc signalling dna damage accumulation and tumour initiation
    Embo Molecular Medicine, 2017
    Co-Authors: Kevin Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Alex Von Kriegsheim, Balazs Győrffy, Mamunur Rashid, Simona Polo, Elena Maspero, Lynsey Vaughan
    Abstract:

    Abstract Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1 , which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1 , we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc , with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc . The increased levels of DNA damage sensitised Huwe1 ‐deficient tumours to DNA‐damaging agents and to deletion of the anti‐apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a Potential Vulnerability of HUWE1 ‐mutated tumours to DNA‐damaging agents and inhibitors of anti‐apoptotic proteins.

  • huwe1 is a critical colonic tumour suppressor gene that prevents myc signalling dna damage accumulation and tumour initiation
    Embo Molecular Medicine, 2017
    Co-Authors: Kevin Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Balazs Győrffy, Mamunur Rashid, Simona Polo, Elena Maspero, Alex Von Kriegsheim, Lynsey Vaughan
    Abstract:

    Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc The increased levels of DNA damage sensitised Huwe1-deficient tumours to DNA-damaging agents and to deletion of the anti-apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a Potential Vulnerability of HUWE1-mutated tumours to DNA-damaging agents and inhibitors of anti-apoptotic proteins.