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P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis

Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2ry14 in human neurofibromas, neurofibroma-derived SC...

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Autores principales: Patritti Cram, Jennifer, Wu, Jianqiang, Coover, Robert A, Rizvi, Tilat A, Chaney, Katherine E, Ravindran, Ramya, Cancelas, Jose A, Spinner, Robert J, Ratner, Nancy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959601/
https://www.ncbi.nlm.nih.gov/pubmed/35311647
http://dx.doi.org/10.7554/eLife.73511
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author Patritti Cram, Jennifer
Wu, Jianqiang
Coover, Robert A
Rizvi, Tilat A
Chaney, Katherine E
Ravindran, Ramya
Cancelas, Jose A
Spinner, Robert J
Ratner, Nancy
author_facet Patritti Cram, Jennifer
Wu, Jianqiang
Coover, Robert A
Rizvi, Tilat A
Chaney, Katherine E
Ravindran, Ramya
Cancelas, Jose A
Spinner, Robert J
Ratner, Nancy
author_sort Patritti Cram, Jennifer
collection PubMed
description Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2ry14 in human neurofibromas, neurofibroma-derived SC precursors (SCPs), mature SCs, and mouse SCPs. Mouse Nf1-/- SCP self-renewal was reduced by genetic or pharmacological inhibition of P2ry14. In a mouse model of NF1, genetic deletion of P2ry14 rescued low cAMP signaling, increased mouse survival, delayed neurofibroma initiation, and improved SC Remak bundles. P2ry14 signals via G(i) to increase intracellular cAMP, implicating P2ry14 as a key upstream regulator of cAMP. We found that elevation of cAMP by either blocking the degradation of cAMP or by using a P2ry14 inhibitor diminished NF1-/- SCP self-renewal in vitro and neurofibroma SC proliferation in in vivo. These studies identify P2ry14 as a critical regulator of SCP self-renewal, SC proliferation, and neurofibroma initiation.
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spelling pubmed-89596012022-03-29 P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis Patritti Cram, Jennifer Wu, Jianqiang Coover, Robert A Rizvi, Tilat A Chaney, Katherine E Ravindran, Ramya Cancelas, Jose A Spinner, Robert J Ratner, Nancy eLife Cancer Biology Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2ry14 in human neurofibromas, neurofibroma-derived SC precursors (SCPs), mature SCs, and mouse SCPs. Mouse Nf1-/- SCP self-renewal was reduced by genetic or pharmacological inhibition of P2ry14. In a mouse model of NF1, genetic deletion of P2ry14 rescued low cAMP signaling, increased mouse survival, delayed neurofibroma initiation, and improved SC Remak bundles. P2ry14 signals via G(i) to increase intracellular cAMP, implicating P2ry14 as a key upstream regulator of cAMP. We found that elevation of cAMP by either blocking the degradation of cAMP or by using a P2ry14 inhibitor diminished NF1-/- SCP self-renewal in vitro and neurofibroma SC proliferation in in vivo. These studies identify P2ry14 as a critical regulator of SCP self-renewal, SC proliferation, and neurofibroma initiation. eLife Sciences Publications, Ltd 2022-03-21 /pmc/articles/PMC8959601/ /pubmed/35311647 http://dx.doi.org/10.7554/eLife.73511 Text en © 2022, Patritti Cram et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Patritti Cram, Jennifer
Wu, Jianqiang
Coover, Robert A
Rizvi, Tilat A
Chaney, Katherine E
Ravindran, Ramya
Cancelas, Jose A
Spinner, Robert J
Ratner, Nancy
P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
title P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
title_full P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
title_fullStr P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
title_full_unstemmed P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
title_short P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
title_sort p2ry14 camp signaling regulates schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959601/
https://www.ncbi.nlm.nih.gov/pubmed/35311647
http://dx.doi.org/10.7554/eLife.73511
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