Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus Journal Article
| Authors: | Li, W.; You, L.; Cooper, J.; Schiavon, G.; Pepe-Caprio, A.; Zhou, L.; Ishii, R.; Giovannini, M.; Hanemann, C. O.; Long, S. B.; Erdjument-Bromage, H.; Zhou, P.; Tempst, P.; Giancotti, F. G. |
| Article Title: | Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus |
| Abstract: | Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth-inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4DCAF1, and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 implement a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlin's ability to interact with or inhibit CRL4DCAF1. Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4DCAF1. © 2010 Elsevier Inc. All rights reserved. |
| Keywords: | controlled study; unclassified drug; gene mutation; human cell; nonhuman; protein function; cell proliferation; animal cell; animals; cells, cultured; enzyme inhibition; gene expression; signaling; cell line; protein binding; cell line, tumor; cancer inhibition; cancer cell; carrier proteins; mesothelioma; active transport, cell nucleus; models, molecular; cell nucleus; gene silencing; ubiquitin protein ligase e3; tumor suppressor protein; merlin; genes, tumor suppressor; humdisease; neurofibromin 2; neurilemoma; ddb1 and cul4 associated factor 1 protein; protein crl4; protein nf2; neurilemmoma |
| Journal Title: | Cell |
| Volume: | 140 |
| Issue: | 4 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2010-02-19 |
| Start Page: | 477 |
| End Page: | 490 |
| Language: | English |
| DOI: | 10.1016/j.cell.2010.01.029 |
| PUBMED: | 20178741 |
| PROVIDER: | scopus |
| PMCID: | PMC2828953 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 15" - "Export Date: 20 April 2011" - "CODEN: CELLB" - "Source: Scopus" |
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