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, Erik S. Knudsen

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4782-4789
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number7
DOIs
StatePublished - Feb 15 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Strobeck, M. W., Reisman, D. N., Gunawardena, R. W., Betz, B. L., Angus, S. P., Knudsen, K. E., Kowalik, T. F., Weissman, B. E., & Knudsen, E. S. (2002). Compensation of BRG-1 function by Brm. Insight into the role of the core SWI·SNF subunits in retinoblastoma tumor suppressor signaling. Journal of Biological Chemistry, 277(7), 4782-4789. https://doi.org/10.1074/jbc.M109532200