Distinct mammalian SWI/SNF chromatin remodeling complexes with opposing roles in cell-cycle control

Abstract

The mammalian SWI/SNF chromatin remodeling complex is becoming increasingly recognized for its role in tumor suppression, based on its ability to regulate accessibility of proliferation‐associated genes to transcription factors. However, understanding the biological role of the complex is complicated because the same complex seemingly plays both positive and negative roles in gene expression. Work described here reveals that a choice between two independently encoded, closely related variants of a major subunit of the ARID protein family determines whether the SWI/SNF complex forms further associations with activator versus repressor complexes. The choice distinguishes assemblies with opposite effects on cell‐cycle activity. The specific complexes control access of factors such as E2F1, Tip60, and HDAC1/2/3 to the promoters of various cell‐cycle‐specific genes, with c‐Myc emerging as a particularly critical target.

Dysregulation of the transcription factors SOX4, CBFB and SMARCC1 correlates with outcome of colorectal cancer

“…In agreement with this, and with a previous report on the subcellular location of SMARCC1 in prostate cancer, we found SMARCC1 to be located in the nucleus (Heeboll et al, 2008). It is worth noting that in recent reports, the SWI/SNF chromatin remodelling complex, in line with our observations (SMARCC1), has become increasingly recognised for its role in tumour suppression (Roberts and Orkin, 2004;Nagl et al, 2007). To our knowledge, CBFB has not previously been associated with tumour suppressor activity.…”

The SWI/SNF complex and cancer

“…BAF250A is lost in two cell lines, C33a and T47D , and may be deficient in as many as 30% of renal carcinomas and 10% of breast carcinomas (Wang et al, 2004a). ARID1A-and ARID1B-containing SWI/SNF complexes appear to have antagonistic effects on cell cycle progression, with ARID1A participating in repression and ARID1B in the induction of key cell cycle regulators such as c-MYC (Nagl et al, 2006(Nagl et al, , 2007. BAF180 (polybromo, PB1, PBRM1)-containing SWI/ SNF complexes have different properties from those that contain BAF250 subunits Lemon et al, 2001;Wang et al, 2004c) and are designated polybromo SWI/SNF complexes or PBAF (Figure 1).…”

E2F-associated chromatin modifiers and cell cycle control

“…The non-catalytic ARID subunits, ARID1A and ARID1B, may dictate functional differences. Indeed, recent studies suggest that the ARID1A subunit of the SWI/SNF complex is required for cell cycle exit, whereas the ARID1B-containing complex is only necessary for cell cycle reentry [32]. Both proteins interact with repressor E2Fs, but only ARID1B interacts specifically with E2F1, an activator E2F.…”