Loss of the INI1 tumor suppressor does not impair the expression of multiple BRG1-dependent genes or the assembly of SWI/SNF enzymes

Doan, Diem N.; Veal, Timothy M.; Yan, Zhijiang; Wang, Weidong; Jones, Stephen N.; Imbalzano, Anthony N.

doi:10.1038/sj.onc.1207472

Cited by 70 publications

(69 citation statements)

References 75 publications

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“…The different tumor phenotypes are probably not due to functional compensation of Brg1 haploinsufficiency by Brm because Brg1 þ /À , Brm À/À double-mutant mice do not develop MRTs or other tumors observed in Snf5 heterozygotes. It has been demonstrated that SNF5 is not required for assembly of mammalian SWI/SNFrelated complexes or BRG1-dependent functions in vitro (Doan et al, 2004), suggesting that Brg1 and Snf5 mutant complexes are stable but compromised in different ways. However, the molecular basis of these differences and how they result in seemingly unrelated tumor phenotypes must still be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Characterization of mammary tumors from Brg1 heterozygous mice

et al. 2007

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Mammalian SWI/SNF-related complexes have been implicated in cancer based on some of the subunits physically interacting with retinoblastoma (RB) and other proteins involved in carcinogenesis. Additionally, several subunits are mutated or not expressed in tumor-derived cell lines. Strong evidence for a role in tumorigenesis in vivo, however, has been limited to SNF5 mutations that result primarily in malignant rhabdoid tumors (MRTs) in humans and MRTs as well as other sarcomas in mice. We previously generated a null mutation of the Brg1 catalytic subunit in the mouse and reported that homozygotes die during embryogenesis. Here, we demonstrate that Brg1 heterozygotes are susceptible to mammary tumors that are fundamentally different than Snf5 tumors. First, mammary tumors are carcinomas not sarcomas. Second, Brg1 þ /À tumors arise because of haploinsufficiency rather than loss of heterozygosity. Third, Brg1 þ /À tumors exhibit genomic instability but not polyploidy based on array comparative genomic hybridization results. We monitored Brg1 þ /À , Brm À/À double-mutant mice but did not observe any tumors resembling those from Snf5 mutants, indicating that the Brg1 þ /À and Snf5 þ /À tumor phenotypes do not differ simply because Brg1 has a closely related paralog whereas Snf5 does not. These findings demonstrate that BRG1 and SNF5 are not functionally equivalent but protect against cancer in different ways. We also demonstrate that Brg1 þ /À mammary tumors have relatively heterogeneous gene expression profiles with similarities and differences compared to other mouse models of breast cancer. The Brg1 þ /À expression profiles are not particularly similar to mammary tumors from Wap-T121 transgenic line where RB is perturbed. We were also unable to detect a genetic interaction between the Brg1 þ /À and Rb þ /À tumor phenotypes. These latter findings do not support a BRG1-RB interaction in vivo. IntroductionMuch work has focused on the role of mammalian SWI/ SNF-related complexes in cancer. SWI/SNF-related subunits physically interact with a number of proteins encoded by tumor-suppressor genes and proto-oncogenes (Muchardt and Yaniv, 2001;Roberts and Orkin, 2004). For example, BRM and BRG1 bind retinoblastoma (RB) and are required to repress the activity of E2F1, inhibit the transcription of cyclins A and E and mediate G 1 cell-cycle arrest in vitro. BRG1 and SNF5 can also act upstream of RB by activating the expression of several cyclin-dependent kinase inhibitors (p15 INK4b , p16 INK4A or p21 CIP1/WAF1 ), which leads to the inhibition of CDK2 and CDK4 and accumulation of the hypophosphorylated form of RB that mediates G 1 arrest.In addition to being associated with cancer-related proteins, the BRM, BRG1, SNF5, BAF155 and BAF250 subunits are mutated or not expressed in various tumor-derived cell lines (Muchardt and Yaniv, 2001). When tumor-derived cell lines are cultured, however, deletions and epigenetic alterations are selected for and accumulate. Because of this caveat, it is crucial to identify and characterize mu...

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Section: Discussionmentioning

confidence: 99%

Characterization of mammary tumors from Brg1 heterozygous mice

et al. 2007

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“…Analyses of knockout mice of each subunit of SWI/SNF complex showed that both Ini1 and BRG1 heterozygotes were predisposed to malignant tumors (Bultman et al, 2000;Klochendler-Yeivin et al, 2000;Barker et al, 2001), but phenotypes of the tumors are quite different. It was also reported that SWI/SNF complex formation and the expression of many BRG1-dependent genes are independent of Ini1 expression (Doan et al, 2004). It is therefore possible that each of Brm, BRG1, and Ini1 subunits could be a component of other distinct protein complexes that manifest their own tumorsuppressing potential.…”

Section: Discussionmentioning

confidence: 99%

The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential

et al. 2005

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The mammalian SWI/SNF chromatin remodeling complex is composed of more than 10 protein subunits, and plays important roles in epigenetic regulation. Each complex includes a single BRG1 or Brm molecule as the catalytic subunit. We previously reported that loss of Brm, but not BRG1, causes transcriptional gene silencing of murine leukemia virus-based retrovirus vectors. To understand the biological function and biogenesis of Brm protein, we examined seven cell lines derived from various human tumors that do not produce Brm protein. We show here that these Brm-deficient cell lines transcribe the Brm genes efficiently as detected by nuclear run-on transcription assay, whereas Brm mRNA and Brm hnRNA were undetectable by reverse transcription-polymerase chain reaction analysis. These results indicate that expression of Brm is strongly and promptly suppressed at the posttranscriptional level, through processing and transport of the primary transcript or through stability of mature Brm mRNA. This suppression was attenuated by transient treatment of these cell lines with HDAC inhibitors probably through indirect mechanism. Importantly, all of the treated cells showed prolonged induction of Brm expression after the removal of HDAC inhibitors, and acquired the ability to maintain retroviral gene expression. These results indicate that these Brm-deficient human tumor cell lines carry a functional Brm gene. Treatment with HDAC inhibitors or introduction of exogenous Brm into Brm-deficient cell lines significantly reduced the oncogenic potential as assessed by colonyforming activity in soft agar or invasion into collagen gel, indicating that, like BRG1, Brm is involved in tumor suppression.

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“…As noted above, BAF47 knockout is the most tumorigenic defect that has been engineered to date. However, SWI/SNF activity is maintained at some level even in the absence of BAF47 (Doan et al, 2004), which seems to function more as an enhancer of remodeling activity, rather than an obligatory component of the chromatin-remodeling complex (Phelan et al, 1999). Conversely, concomitant loss of both BRG1 and BRM should result in the complete loss of SWI/SNF-mediated ATP-dependent chromatinremodeling activity, with attendant degradation of the several tumor suppressor functions that require SWI/ SNF.…”

Section: Transgenic Knockout Of Brm or Brg1 Enhances Transformationmentioning

confidence: 99%

The SWI/SNF complex and cancer

2009

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The mammalian SWI/SNF complexes mediate ATPdependent chromatin remodeling processes that are critical for differentiation and proliferation. Not surprisingly, loss of SWI/SNF function has been associated with malignant transformation, and a substantial body of evidence indicates that several components of the SWI/SNF complexes function as tumor suppressors. This review summarizes the evidence that underlies this conclusion, with particular emphasis upon the two catalytic subunits of the SWI/SNF complexes, BRM, the mammalian ortholog of SWI2/SNF2 in yeast and brahma in Drosophila, and Brahma-related gene-1 (BRG1).

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Loss of the INI1 tumor suppressor does not impair the expression of multiple BRG1-dependent genes or the assembly of SWI/SNF enzymes

Cited by 70 publications

References 75 publications

Characterization of mammary tumors from Brg1 heterozygous mice

Characterization of mammary tumors from Brg1 heterozygous mice

The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential

The SWI/SNF complex and cancer

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