Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis.

Fine-tuned Notch and Hedgehog signalling pathways via attenuators and dampers have long been recognized as important mechanisms to ensure the proper size and differentiation of many organs and tissues. This notion is further supported by identification of mutations in these pathways in human cancer...

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Autores principales:	Vanina G Da Ros, Irene Gutierrez-Perez, Dolors Ferres-Marco, Maria Dominguez
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/14de1cf1f28d4a7393e46f3ec3003f04
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spelling	oai:doaj.org-article:14de1cf1f28d4a7393e46f3ec3003f042021-11-18T05:37:07ZDampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis.1544-91731545-788510.1371/journal.pbio.1001554https://doaj.org/article/14de1cf1f28d4a7393e46f3ec3003f042013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23667323/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Fine-tuned Notch and Hedgehog signalling pathways via attenuators and dampers have long been recognized as important mechanisms to ensure the proper size and differentiation of many organs and tissues. This notion is further supported by identification of mutations in these pathways in human cancer cells. However, although it is common that the Notch and Hedgehog pathways influence growth and patterning within the same organ through the establishment of organizing regions, the cross-talk between these two pathways and how the distinct organizing activities are integrated during growth is poorly understood. Here, in an unbiased genetic screen in the Drosophila melanogaster eye, we found that tumour-like growth was provoked by cooperation between the microRNA miR-7 and the Notch pathway. Surprisingly, the molecular basis of this cooperation between miR-7 and Notch converged on the silencing of Hedgehog signalling. In mechanistic terms, miR-7 silenced the interference hedgehog (ihog) Hedgehog receptor, while Notch repressed expression of the brother of ihog (boi) Hedgehog receptor. Tumourigenesis was induced co-operatively following Notch activation and reduced Hedgehog signalling, either via overexpression of the microRNA or through specific down-regulation of ihog, hedgehog, smoothened, or cubitus interruptus or via overexpression of the cubitus interruptus repressor form. Conversely, increasing Hedgehog signalling prevented eye overgrowth induced by the microRNA and Notch pathway. Further, we show that blocking Hh signal transduction in clones of cells mutant for smoothened also enhance the organizing activity and growth by Delta-Notch signalling in the wing primordium. Together, these findings uncover a hitherto unsuspected tumour suppressor role for the Hedgehog signalling and reveal an unanticipated cooperative antagonism between two pathways extensively used in growth control and cancer.Vanina G Da RosIrene Gutierrez-PerezDolors Ferres-MarcoMaria DominguezPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 11, Iss 5, p e1001554 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Vanina G Da Ros Irene Gutierrez-Perez Dolors Ferres-Marco Maria Dominguez Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis.
description	Fine-tuned Notch and Hedgehog signalling pathways via attenuators and dampers have long been recognized as important mechanisms to ensure the proper size and differentiation of many organs and tissues. This notion is further supported by identification of mutations in these pathways in human cancer cells. However, although it is common that the Notch and Hedgehog pathways influence growth and patterning within the same organ through the establishment of organizing regions, the cross-talk between these two pathways and how the distinct organizing activities are integrated during growth is poorly understood. Here, in an unbiased genetic screen in the Drosophila melanogaster eye, we found that tumour-like growth was provoked by cooperation between the microRNA miR-7 and the Notch pathway. Surprisingly, the molecular basis of this cooperation between miR-7 and Notch converged on the silencing of Hedgehog signalling. In mechanistic terms, miR-7 silenced the interference hedgehog (ihog) Hedgehog receptor, while Notch repressed expression of the brother of ihog (boi) Hedgehog receptor. Tumourigenesis was induced co-operatively following Notch activation and reduced Hedgehog signalling, either via overexpression of the microRNA or through specific down-regulation of ihog, hedgehog, smoothened, or cubitus interruptus or via overexpression of the cubitus interruptus repressor form. Conversely, increasing Hedgehog signalling prevented eye overgrowth induced by the microRNA and Notch pathway. Further, we show that blocking Hh signal transduction in clones of cells mutant for smoothened also enhance the organizing activity and growth by Delta-Notch signalling in the wing primordium. Together, these findings uncover a hitherto unsuspected tumour suppressor role for the Hedgehog signalling and reveal an unanticipated cooperative antagonism between two pathways extensively used in growth control and cancer.
format	article
author	Vanina G Da Ros Irene Gutierrez-Perez Dolors Ferres-Marco Maria Dominguez
author_facet	Vanina G Da Ros Irene Gutierrez-Perez Dolors Ferres-Marco Maria Dominguez
author_sort	Vanina G Da Ros
title	Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis.
title_short	Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis.
title_full	Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis.
title_fullStr	Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis.
title_full_unstemmed	Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis.
title_sort	dampening the signals transduced through hedgehog via microrna mir-7 facilitates notch-induced tumourigenesis.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/14de1cf1f28d4a7393e46f3ec3003f04
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Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis.

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