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J. Biol. Chem., Vol. 277, Issue 7, 4782-4789, February 15, 2002

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Compensation of BRG-1 Function by Brm
INSIGHT INTO THE ROLE OF THE CORE SWI·SNF SUBUNITS IN RETINOBLASTOMA TUMOR SUPPRESSOR SIGNALING^*

Matthew W. Strobeck^§, David N. Reisman^¶, Ranjaka W. Gunawardena, Bryan L. Betz^¶, Steven P. Angus, Karen E. Knudsen, Timothy F. Kowalik^**, Bernard E. Weissman^¶, and Erik S. Knudsen

From the  Department of Cell Biology, University of Cincinnati College of Medicine, Vontz Center for Molecular Studies, Cincinnati, Ohio 45267-0521, ^¶ Department of Pathology and Laboratory Medicine and  The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, and ^** Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655

The BRG-1 subunit of the SWI·SNF complex is involved in chromatin remodeling and has been implicated in the action of the retinoblastoma tumor suppressor (RB). Given the importance of BRG-1 in RB function, germ line BRG-1 mutations in tumorigenesis may be tantamount to RB inactivation. Therefore, in this study we assessed the behavior of cells harboring discrete BRG-1 alleles for the RB-signaling pathway. Using p16ink4a, an upstream activator of endogenous RB, or a constitutively active RB construct (PSM-RB), we determined that the majority of tumor lines with germ line defects in BRG-1 were sensitive to RB-mediated cell cycle arrest. By contrast, A427 (lung carcinoma) cells were resistant to expression of p16ink4a and PSM-RB. Analysis of the SWI·SNF subunits in the different tumor lines revealed that A427 are deficient for BRG-1 and its homologue, Brm, whereas RB-sensitive cell lines retained Brm expression. Similarly, the RB-resistant SW13 and C33A cell lines were also deficient for both BRG-1/Brm. Reintroduction of either BRG-1 or Brm into A427 or C33A cells restored RB-mediated signaling to cyclin A to cause cell cycle arrest. Consistent with this compensatory role, we observed that Brm could also drive expression of CD44. We also determined that loss of these core SWI·SNF subunits renders SW13 cells resistant to activation of the RB pathway by the chemotherapeutic agent cisplatin, since reintroduction of either BRG-1 or Brm into SW13 cells restored the cisplatin DNA-damage checkpoint. Together, these data demonstrate that Brm can compensate for BRG-1 loss as pertains to RB sensitivity.

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