When the SWI/SNF complex remodels … the cell cycle

Abstract

Mammalian cells contain several chromatin-remodeling complexes associated with the Brm and Brg1 helicaselike proteins. These complexes likely represent the functional homologs of the SWI/SNF and RSC complexes found in Saccharomyces cerevisiae. The mammalian chromatin-remodeling complexes are involved in both activation and repression of a variety of genes. Several lines of evidence also indicate that they play a speci®c role in the regulation of cell growth. Brm is down-regulated by ras signaling and its forced reexpression suppresses transformation by this oncogene. Besides, the Brg1 gene is silenced or mutated in several tumors cell lines and a Brg1-associated complex was recently found to co-purify with BRCA1, involved in breast and ovarian cancers. Finally, the gene encoding SNF5/Ini1, a subunit common to all mammalian SWI/ SNF complexes, is inactivated in rhabdoid sarcomas, a very aggressive form of pediatric cancer. The current review will address observations made upon inactivation of Brm, Brg1 and SNF5/Ini1 by homologous recombination in the mouse, as well as the possible implication of these factors in the regulation of the Retinoblastoma pRb-mediated repression of the transcription factor E2F. Oncogene (2001) 20, 3067 ± 3075.

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

“…The BRM gene in BRG1/BRM-deficient cell lines is not mutated We and others have noted that BRG1 and BRM protein levels are consistently lost together in a variety of cancer cell lines (Muchardt and Yaniv, 2001;Reisman et al, 2002). BRG1 has been found to be mutated (Wong et al, 2000)) in these cell lines, but the various mechanisms that might underlie BRM loss have not been elucidated.…”

“…The frequency of BRM loss in primary cancers other than lung has not yet been determined, although loss of BRM in a variety of cancer cell lines has been reported (Muchardt and Yaniv, 2001;Reisman et al, 2003). We immunostained six different high-density, tissue-specific Figure 4 (a) MG2-13 cells were treated with butyrate for 72 h and then butyrate was removed.…”

“…This complex is recruited to DNA by a variety of transcription factors and is required for the activity of a diverse number of important signaling pathways (Muchardt and Yaniv, 2001;KlochendlerYeivin et al, 2002). The SWI/SNF complex's broad role in gene regulation is perhaps best demonstrated thus far in yeast, where its function is essential for regulation of at least 7% of genes (Sudarsanam et al, 2000).…”

“…SWI/ SNF contains one of two key ATPase subunits, either Brahma (BRM) or BRM-related gene 1 (BRG1) and 9-12 BRG1/BRM-associated factors (Wang et al, 1996), which assemble into at least three different 2 MDa complexes. The SWI/SNF complex was first linked to tumorigenesis when the BAF47 subunit was found to be a bona fide tumor suppressor (Muchardt and Yaniv, 2001;Roberts and Orkin, 2004). The loss of BAF47 expression has been shown to be a key event in the development of certain sarcomas, and homozygous deletion of this gene is highly tumorigenic in mice.…”

The SWI/SNF complex and cancer

“…Its loss occurs in both familial and sporadic renal and extra-renal rhabdoid tumors, as well as in certain central nervous system tumors (Biegel et al, 2002;Biegel and Pollack, 2004;Bourdeaut et al, 2007); however, not more than 50 patients have been identified with this defect, and loss of BAF47 has very infrequently been observed in any adult tumor (Grand et al, 1999;Manda et al, 2000;Yuge et al, 2000;DeCristofaro et al, 2001). Instead, in adult tumors, the major cancer defect in SWI/SNF appears to be the loss of BRG1, BRM or both (Muchardt and Yaniv, 2001). This appears to occur between 10 and 20% of a variety of tumor types (Reisman et al, 2003;Glaros et al, 2007).…”