Human SWI-SNF Component BRG1 Represses Transcription of the c-fos Gene

Abstract

-13 cells potentiated transcriptional activation by the glucocorticoid receptor, which is known to require SWI-SNF function. BRG1 also specifically repressed transcription from a transfected c-fos promoter and correspondingly blocked transcriptional activation of the endogenous c-fos gene. Mutation of lysine residue 798 in the DNA-dependent ATPase domain of BRG1 significantly reduced its ability to repress c-fos transcription. Repression by BRG1 required the cyclic AMP response element of the c-fos promoter but not nearby binding sites for Sp1, YY1, or TFII-I. Using human C33A cervical carcinoma cells, which lack BRG1 and also express a nonfunctional Rb protein, transcriptional repression by BRG1 was weak unless wild-type Rb was also supplied. Interestingly, Rb-dependent repression by BRG1 was found to take place through a pathway that is independent of transcription factor E2F.The modification of chromatin structure is increasingly recognized to be an important facet of transcriptional regulation. Such alterations likely occur in concert with the actions of the general transcription factors and promoter-specific activators and repressors in order to allow regulatory changes to take place. Several multiprotein complexes with roles in this kind of regulation have been identified, including the yeast SAGA (23,72) and RSC (9) complexes, the Drosophila ISWI-containing complexes (16,29,67,69), and the yeast and human SWI-SNF complexes (ySWI-SNF and hSWI-SNF) (8,14,28,32,35,37,50,55,73,74). The regulation of chromatin structure is likely to influence specific cellular processes that rely heavily on transcriptional events, including the control of cellular proliferation.Several studies have suggested a role for hSWI-SNF components BRG1 (32), hBRM (50), and hSNF5-INI1 (49) in the control of cellular proliferation. BRG1 and hBRM, human homologues of yeast SNF2, bind to members of the retinoblastoma (Rb) tumor suppressor protein family and can trigger cellular growth arrest (15,32,61,62). Recently, the hSNF5-INI1-encoding gene was found to be mutated in multiple malignant rhabdoid tumors, strongly suggesting that hSWI-SNF has a tumor suppressor function (71). In addition, we have reported that the N-terminal domain of the adenovirus E1A oncoprotein specifically blocks SWI-SNF-dependent transcription in budding yeast, suggesting that disruption of human and mouse SWI-SNF function may be important in oncogenic transformation by E1A (46).The ySWI-SNF and hSWI-SNF complexes have been studied extensively in vitro and have been demonstrated to trigger chromatin remodeling and facilitation of sequence-specific DNA binding (reviewed in references 7, 31, and 35). In addition, genetic approaches have resulted in the identification of several yeast cellular genes whose transcriptional regulation requires a functional SWI-SNF complex (10,38,39,41,56). In higher eukaryotic systems, transfected promoters under the control of the glucocorticoid receptor (GR) (17, 50, 61) or transcription factor E2F (66) have been shown to be regulated b...

SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity

“…Findings from multiple laboratories have suggested that deletion/loss of Brg1 may contribute to the genesis of cancer (Murphy et al, 1999;Lee et al, 2002); however, the underlying mechanism for this process is unclear. The data presented here indicate that loss of Brg1 results in aberrant mitotic progression and provides evidence of genomic instability.…”

“…Our data support the notion that Brg1 deficiency can be overcome by virtue of additional stochastic events; however, this process was highly sporadic even in the context of immortalized 3T3 populations and selection for Brg1 deletion. Thus, tumor cell lines and potentially other Brg1-deficient cell types, presumably use compensatory mechanisms to bypass the requirement that we observed.Findings from multiple laboratories have suggested that deletion/loss of Brg1 may contribute to the genesis of cancer (Murphy et al, 1999;Lee et al, 2002); however, the underlying mechanism for this process is unclear. The data presented here indicate that loss of Brg1 results in aberrant mitotic progression and provides evidence of genomic instability.…”

Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging

“…Other more distantly related enzymes include human hBrm, Brg1 and the CHD family (CHD1-7). Of note, human hBrm and Brg1 are two candidate tumor suppressor genes that are implicated in repression of E2F target genes and induction of cell differentiation and senescence, through physical and functional interactions with the pRB protein (33,38,56,76,85,104,105,115,124,134,142). Since E2F target genes are incorporated into SAHF and formation of SAHF requires an intact pRB pathway (88,140), hBrm and/or Brg1 might be involved in SAHF assembly, perhaps through deposition of macroH2A.…”

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

“…Complexes containing BRG1 have been shown to be required for cell cycle control, apoptosis and differentiation in several biological systems (Dunaief et al, 1994;Murphy et al, 1999;Bultman et al, 2000;Reisman et al, 2002;Martens and Winston, 2003;Hendricks et al, 2004;de la Serna et al, 2006). Homozygous knockout mice for the Brg1 gene die during the embryonic stage, whereas heterozygotic survivors are prone to tumors (Bultman et al, 2000;Saha et al, 2006;de la Serna et al, 2006).…”

“…Homozygous knockout mice for the Brg1 gene die during the embryonic stage, whereas heterozygotic survivors are prone to tumors (Bultman et al, 2000;Saha et al, 2006;de la Serna et al, 2006). BRG1 protein can interact with different proteins involved in regulation of transcription, such as factors involved in myeloid, erythrocyte, lymphocyte, muscle, neural and adipocyte commitment and/or differentiation (Dunaief et al, 1994;Murphy et al, 1999;Bultman et al, 2000;Reisman et al, 2002;Martens and Winston, 2003;Hendricks et al, 2004;Saha et al, 2006;de la Serna et al, 2006). The BRG1 chromatin remodeling protein can associate with numerous chromatin-modifying complexes, including transcription co-activators and corepressors.…”