Cell Biology

Familial Ties in the Nucleus

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Science  19 Mar 2010:
Vol. 327, Issue 5972, pp. 1431->1431
DOI: 10.1126/science.327.5972.1431-b

Inherited mutations in tumor suppressor genes cause an increased risk of developing familial cancer syndromes. Many of these familial tumor suppressor genes are also frequently mutated in somatic cancers. The tumor suppressor gene NF2 is mutated in the familial cancer syndrome neurofibromatosis type 2, which causes multiple brain tumors such as schwannomas and meningiomas. NF2 encodes the protein Merlin, which appears to link cell adhesion receptors at the cell surface to the actin cytoskeleton and is thus poised to inhibit mitogenic signaling downstream of integrins and adhesins. Now, Li et al. have identified a very different function for Merlin, this time in the nucleus. Endogenous Merlin was observed in the nucleus of multiple cell types by virtue of its binding to an E3 ubiquitin ligase, CRL4DCAF1. The binding of CRL4DCAF1 to Merlin inhibited the ubiquitin ligase activity and suppressed cell proliferation. Tumor-derived mutations in NF2 prevented Merlin from inhibiting CRL4DCAF1 activity, and CRL4DCAF1 was required for the malignant properties of primary human tumor cells derived from NF2 patients, thus providing a possible drug target.

Cell 140, 477 (2010).

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