BRG-1 is required for RB-mediated cell cycle arrest

Matthew W. Strobeck, Karen E. Knudsen, Anne F. Fribourg, Marc F. DeCristofaro, Bernard E. Weissman, Anthony N. Imbalzano, Erik S. Knudsen

Research output: Contribution to journalArticle

197 Citations (Scopus)

Abstract

The antiproliferative action of the retinoblastoma tumor suppressor protein, RB, is disrupted in the majority of human cancers. Disruption of RB activity occurs through several disparate mechanisms, including viral oncoprotein binding, deregulated RB phosphorylation, and mutation of the RB gene. Here we report disruption of RB-signaling in tumor cells through loss of a critical cooperating factor. We have previously reported that C33A cells fail to undergo cell cycle inhibition in the presence of constitutively active RB (PSM-RB). To determine how C33A cells evade RB-mediated arrest, cell fusion experiments were performed with RB-sensitive cells. The resulting fusions were arrested by PSM-RB, indicating that C33A cells lack a factor required for RB-mediated cell cycle inhibition. C33A cells are deficient in BRG-1, a SWI/SNF family member known to stimulate RB activity. Consistent with BRG-1 deficiency underlying resistance to RB-mediated arrest, we identified two other BRG-1-deficient cell lines (SW13 and PANC-1) and demonstrate that these tumor lines are also resistant to cell cycle inhibition by PSM-RB and p16ink4a, which activates endogenous RB. In cell lines lacking BRG-1, we noted a profound defect in RB-mediated repression of the cyclin A promoter. This deficiency in RB-mediated transcriptional repression and cell cycle inhibition was rescued through ectopic coexpression of BRG-1. We also demonstrate that 3T3-derived cells, which inducibly express a dominant-negative BRG-1, arrest by PSM-RB and p16ink4a in the absence of dominant-negative BRG-1 expression; however, cell cycle arrest was abrogated on induction of dominant-negative BRG-1. These findings demonstrate that BRG- 1 loss renders cells resistant to RB-mediated cell cycle progression, and that disruption of RB signaling through loss of cooperating factors occurs in cancer cells.

Original languageEnglish (US)
Pages (from-to)7748-7753
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number14
DOIs
StatePublished - Jul 5 2000

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Cell Cycle Checkpoints
Cell Cycle
Neoplasms
Tumor Suppressor Proteins
Cyclin A
Cell Line
3T3 Cells
Retinoblastoma Protein
Cell Fusion
Oncogene Proteins
Phosphorylation
Mutation
Inhibition (Psychology)
Genes

Keywords

  • Cdk
  • Cyclins
  • SWI/SNF

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Strobeck, M. W., Knudsen, K. E., Fribourg, A. F., DeCristofaro, M. F., Weissman, B. E., Imbalzano, A. N., & Knudsen, E. S. (2000). BRG-1 is required for RB-mediated cell cycle arrest. Proceedings of the National Academy of Sciences of the United States of America, 97(14), 7748-7753. https://doi.org/10.1073/pnas.97.14.7748

BRG-1 is required for RB-mediated cell cycle arrest. / Strobeck, Matthew W.; Knudsen, Karen E.; Fribourg, Anne F.; DeCristofaro, Marc F.; Weissman, Bernard E.; Imbalzano, Anthony N.; Knudsen, Erik S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 14, 05.07.2000, p. 7748-7753.

Research output: Contribution to journalArticle

Strobeck, MW, Knudsen, KE, Fribourg, AF, DeCristofaro, MF, Weissman, BE, Imbalzano, AN & Knudsen, ES 2000, 'BRG-1 is required for RB-mediated cell cycle arrest', Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 14, pp. 7748-7753. https://doi.org/10.1073/pnas.97.14.7748
Strobeck MW, Knudsen KE, Fribourg AF, DeCristofaro MF, Weissman BE, Imbalzano AN et al. BRG-1 is required for RB-mediated cell cycle arrest. Proceedings of the National Academy of Sciences of the United States of America. 2000 Jul 5;97(14):7748-7753. https://doi.org/10.1073/pnas.97.14.7748
Strobeck, Matthew W. ; Knudsen, Karen E. ; Fribourg, Anne F. ; DeCristofaro, Marc F. ; Weissman, Bernard E. ; Imbalzano, Anthony N. ; Knudsen, Erik S. / BRG-1 is required for RB-mediated cell cycle arrest. In: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; Vol. 97, No. 14. pp. 7748-7753.
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