NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation
| Autor: | Robert F. Hennigan, Yoko Nakai, Yi Zheng, Emily E. Bosco, Nancy Ratner |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
rac1 GTP-Binding Protein
Cancer Research neurofibromatosis type 2 proliferation Biology Article Small hairpin RNA Mice otorhinolaryngologic diseases Genetics Animals Molecular Biology Transcription factor Cells Cultured Cell Proliferation Neurofibromin 2 NF2/merlin Contact Inhibition Neuropeptides Wnt signaling pathway LRP6 Contact inhibition LRP5 wnt signaling rac GTP-Binding Proteins Cell biology Wnt Proteins Merlin (protein) Signal transduction Rac1 Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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