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Molecular and Cellular Biology, March 2005, p. 2384-2394, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2384-2394.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The NF2 Tumor Suppressor Gene Product, Merlin, Inhibits Cell Proliferation and Cell Cycle Progression by Repressing Cyclin D1 Expression

Guang-Hui Xiao,1 Ryan Gallagher,1 Justin Shetler,1 Kristine Skele,1 Deborah A. Altomare,1 Richard G. Pestell,2 Suresh Jhanwar,3 and Joseph R. Testa1*

Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania,1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C.,2 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York3

Received 14 September 2004/ Returned for modification 25 October 2004/ Accepted 7 December 2004

Inactivation of the NF2 tumor suppressor gene has been observed in certain benign and malignant tumors. Recent studies have demonstrated that merlin, the product of the NF2 gene, is regulated by Rac/PAK signaling. However, the mechanism by which merlin acts as a tumor suppressor has remained obscure. In this report, we show that adenovirus-mediated expression of merlin in NF2-deficient tumor cells inhibits cell proliferation and arrests cells at G1 phase, concomitant with decreased expression of cyclin D1, inhibition of CDK4 activity, and dephosphorylation of pRB. The effect of merlin on cell cycle progression was partially overridden by ectopic expression of cyclin D1. RNA interference experiments showed that silencing of the endogenous NF2 gene results in upregulation of cyclin D1 and S-phase entry. Furthermore, PAK1-stimulated cyclin D1 promoter activity was repressed by cotransfection of NF2, and PAK activity was inhibited by expression of merlin. Interestingly, the S518A mutant form of merlin, which is refractory to phosphorylation by PAK, was more efficient than the wild-type protein in inhibiting cell cycle progression and in repressing cyclin D1 promoter activity. Collectively, our data indicate that merlin exerts its antiproliferative effect, at least in part, via repression of PAK-induced cyclin D1 expression, suggesting a unifying mechanism by which merlin inactivation might contribute to the overgrowth seen in both noninvasive and malignant tumors.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111. Phone: (215) 728-2610. Fax: (215) 214-1623. E-mail: Joseph.Testa{at}fccc.edu.

Molecular and Cellular Biology, March 2005, p. 2384-2394, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2384-2394.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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