Compensation of BRG-1 Function by Brm

Abstract

The BRG-1 subunit of the SWI⅐SNF 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 SWI⅐SNF 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 SWI⅐SNF 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.

The CCAAT Enhancer-binding Protein α (C/EBPα) Requires a SWI/SNF Complex for Proliferation Arrest

“…In a subset of mammalian SWI/SNF complexes, Brg1 is the ATPase subunit instead of Brm (49, 54 highly homologous proteins and were found to be at least partially redundant in the regulation of the cell cycle in several studies in cell culture (32,35,36,(55)(56)(57). However, the knockout of Brg1 or Brm in mice produce different phenotypes that indicate differences in their function (33,38).…”

Hierarchical Requirement of SWI/SNF in Retinoblastoma Tumor Suppressor-mediated Repression of Plk1

“…cyclin A) (31,34), the action of SWI/SNF in Plk1 regulation was investigated. The SW13 cell line does not express the BRG1 and BRM ATPases requisite for SWI/SNF activity, whereas TSUPr-1 cells express BRM and are sensitive to RB-mediated signaling (32). To activate the endogenous RB pathway, adenoviral transduction of p16ink4a that maintains RB in its hypophosphorylated/active state was utilized.…”

“…The activity of the core ATPase subunit is required by the SWI/SNF complex to regulate gene transcription (35,37,38). Prior studies have demonstrated that the combined losses of BRG1 and BRM result in resistance to the activation of the RB pathway and aberrant cell cycle progression (32,33). Additionally, the loss of SWI/SNF activity is associated with a failure of RB to elicit transcriptional repression of specific targets (e.g.…”

“…Transcriptional repression is viewed as requisite for RB function in tumor suppression based on genetic and biochemical data (29,30). Additionally, we and others have found that the loss of SWI/SNF chromatin remodeling factors compromises RB-mediated transcriptional repression (31)(32)(33)(34).…”

The Activity of p53 Is Differentially Regulated by Brm- and Brg1-containing SWI/SNF Chromatin Remodeling Complexes

“…For example, both Brm and Brg1 are required for activation of genes such as CD44 (10) and EPO (11) and interact with prohibitin (12) and TopBP (13) for transcriptional repression. Moreover, Brg1 can functionally replace Brm and vice versa (14). Nevertheless, the presence of Brm and Brg1 in an SWI/SNF chromatin remodeling complex is mutually exclusive, and functional differences between Brm and Brg1 have been implicated from in vitro and in vivo studies.…”