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Molecular and Cellular Biology, July 2006, p. 5360-5372, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02464-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Stabilization of the Retinoblastoma Protein by A-Type Nuclear Lamins Is Required for INK4A-Mediated Cell Cycle Arrest{dagger}

Ryan T. Nitta,1 Samantha A. Jameson,1 Brian A. Kudlow,1,2 Lindus A. Conlan,1 and Brian K. Kennedy1*

Department of Biochemistry,1 Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 981952

Received 23 December 2005/ Returned for modification 24 January 2006/ Accepted 14 April 2006

Mutations in the LMNA gene, which encodes all A-type lamins, including lamin A and lamin C, cause a variety of tissue-specific degenerative diseases termed laminopathies. Little is known about the pathogenesis of these disorders. Previous studies have indicated that A-type lamins interact with the retinoblastoma protein (pRB). Here we probe the functional consequences of this association and further examine links between nuclear structure and cell cycle control. Since pRB is required for cell cycle arrest by p16ink4a, we tested the responsiveness of multiple lamin A/C-depleted cell lines to overexpression of this CDK inhibitor and tumor suppressor. We find that the loss of A-type lamin expression results in marked destabilization of pRB. This reduction in pRB renders cells resistant to p16ink4a-mediated G1 arrest. Reintroduction of lamin A, lamin C, or pRB restores p16ink4a-responsiveness to Lmna–/– cells. An array of lamin A mutants, representing a variety of pathologies as well as lamin A processing mutants, was introduced into Lmna–/– cells. Of these, a mutant associated with mandibuloacral dysplasia (MAD R527H), as well as two lamin A processing mutants, but not other disease-associated mutants, failed to restore p16ink4a responsiveness. Although our findings do not rule out links between altered pRB function and laminopathies, they fail to support such an assertion. These findings do link lamin A/C to the functional activation of a critical tumor suppressor pathway and further the possibility that somatic mutations in LMNA contribute to tumor progression.

* Corresponding author. Mailing address: Department of Biochemistry, University of Washington, Seattle, WA 98195. Phone: (206) 685-0111. Fax: (206) 685-1792. E-mail: bkenn{at}u.washington.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2006, p. 5360-5372, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02464-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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