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NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation

The neurofibromatosis type 2 (NF2) tumor suppressor gene encodes merlin, a membrane/cytoskeleton protein necessary for maintenance of contact inhibition of growth in cells. Biallelic inactivation of NF2 is known to cause multiple cancers in both humans and mice. However, the mechanism through which...

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Autores principales: Bosco, Emily E., Nakai, Yoko, Hennigan, Robert F., Ratner, Nancy, Zheng, Yi
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861729/
https://www.ncbi.nlm.nih.gov/pubmed/20154721
http://dx.doi.org/10.1038/onc.2010.20
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author Bosco, Emily E.
Nakai, Yoko
Hennigan, Robert F.
Ratner, Nancy
Zheng, Yi
author_facet Bosco, Emily E.
Nakai, Yoko
Hennigan, Robert F.
Ratner, Nancy
Zheng, Yi
author_sort Bosco, Emily E.
collection PubMed
description The neurofibromatosis type 2 (NF2) tumor suppressor gene encodes merlin, a membrane/cytoskeleton protein necessary for maintenance of contact inhibition of growth in cells. Biallelic inactivation of NF2 is known to cause multiple cancers in both humans and mice. However, the mechanism through which merlin exerts its tumor suppressive function remains obscure. In this report we reveal that NF2 knockout mouse embryonic fibroblasts (MEFs) lost contact inhibition of cell proliferation and contained significantly increased canonical Wnt signaling. Inhibition of Rac1, whose activity is inversely regulated by NF2, through the use of a dominant negative mutant, small hairpin RNA, or a small molecule inhibitor in the NF2-deficient cells, was able to suppress the elevated Wnt signals as shown by reduced activity of the T-cell factor 4 (TCF4) transcription factor. Dominant negative TCF4 or Rac1 mutant, as well as a small molecule inhibition of Wnt, were able to curb the NF2 deficiency-elicited cell proliferation at the confluent state. Thus, Rac1-mediated canonical Wnt signaling is essential for the loss of contact inhibition in NF2-deficient cells.
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spelling pubmed-28617292010-10-29 NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation Bosco, Emily E. Nakai, Yoko Hennigan, Robert F. Ratner, Nancy Zheng, Yi Oncogene Article The neurofibromatosis type 2 (NF2) tumor suppressor gene encodes merlin, a membrane/cytoskeleton protein necessary for maintenance of contact inhibition of growth in cells. Biallelic inactivation of NF2 is known to cause multiple cancers in both humans and mice. However, the mechanism through which merlin exerts its tumor suppressive function remains obscure. In this report we reveal that NF2 knockout mouse embryonic fibroblasts (MEFs) lost contact inhibition of cell proliferation and contained significantly increased canonical Wnt signaling. Inhibition of Rac1, whose activity is inversely regulated by NF2, through the use of a dominant negative mutant, small hairpin RNA, or a small molecule inhibitor in the NF2-deficient cells, was able to suppress the elevated Wnt signals as shown by reduced activity of the T-cell factor 4 (TCF4) transcription factor. Dominant negative TCF4 or Rac1 mutant, as well as a small molecule inhibition of Wnt, were able to curb the NF2 deficiency-elicited cell proliferation at the confluent state. Thus, Rac1-mediated canonical Wnt signaling is essential for the loss of contact inhibition in NF2-deficient cells. 2010-02-15 2010-04-29 /pmc/articles/PMC2861729/ /pubmed/20154721 http://dx.doi.org/10.1038/onc.2010.20 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Bosco, Emily E.
Nakai, Yoko
Hennigan, Robert F.
Ratner, Nancy
Zheng, Yi
NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation
title NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation
title_full NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation
title_fullStr NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation
title_full_unstemmed NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation
title_short NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation
title_sort nf2-deficient cells depend on the rac1-canonical wnt signaling pathway to promote the loss of contact inhibition of proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861729/
https://www.ncbi.nlm.nih.gov/pubmed/20154721
http://dx.doi.org/10.1038/onc.2010.20
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