Identifying biological pathways that underlie primordial short stature using network analysis

Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and...

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Autores principales: Hanson, Dan, Stevens, Adam, Murray, Philip G, Black, Graeme C M, Clayton, Peter E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bioscientifica Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045235/
https://www.ncbi.nlm.nih.gov/pubmed/24711643
http://dx.doi.org/10.1530/JME-14-0029
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author Hanson, Dan
Stevens, Adam
Murray, Philip G
Black, Graeme C M
Clayton, Peter E
author_facet Hanson, Dan
Stevens, Adam
Murray, Philip G
Black, Graeme C M
Clayton, Peter E
author_sort Hanson, Dan
collection PubMed
description Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M ‘interactome’, to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.
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spelling pubmed-40452352014-06-05 Identifying biological pathways that underlie primordial short stature using network analysis Hanson, Dan Stevens, Adam Murray, Philip G Black, Graeme C M Clayton, Peter E J Mol Endocrinol Research Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M ‘interactome’, to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. Bioscientifica Ltd 2014-06 /pmc/articles/PMC4045235/ /pubmed/24711643 http://dx.doi.org/10.1530/JME-14-0029 Text en © 2014 The authors http://creativecommons.org/licenses/by/3.0/deed.en_GB This work is licensed under a Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/deed.en_GB)
spellingShingle Research
Hanson, Dan
Stevens, Adam
Murray, Philip G
Black, Graeme C M
Clayton, Peter E
Identifying biological pathways that underlie primordial short stature using network analysis
title Identifying biological pathways that underlie primordial short stature using network analysis
title_full Identifying biological pathways that underlie primordial short stature using network analysis
title_fullStr Identifying biological pathways that underlie primordial short stature using network analysis
title_full_unstemmed Identifying biological pathways that underlie primordial short stature using network analysis
title_short Identifying biological pathways that underlie primordial short stature using network analysis
title_sort identifying biological pathways that underlie primordial short stature using network analysis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045235/
https://www.ncbi.nlm.nih.gov/pubmed/24711643
http://dx.doi.org/10.1530/JME-14-0029
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