Disease relevance of Smarcb1

• We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors [1].

High impact information on Smarcb1

• We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi/Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5 [1].
• Our findings constitute persuasive genetic evidence that Snf5, a core member of the Swi/Snf chromatin-remodeling complex, functions as a tumor suppressor gene, and, moreover, Snf5 heterozygotes provide a murine model of this lethal pediatric cancer [2].
• Here we report that Snf5 is widely expressed during embryogenesis with focal areas of high-level expression in the mandibular portion of the first branchial arch and central nervous system [2].
• The majority of MRT samples and cell lines have sustained biallelic inactivating mutations of the hSNF5 (integrase interactor 1) gene, suggesting that hSNF5 may act as a tumor suppressor [2].
• We demonstrate that Snf5 deletion in primary fibroblasts impairs cell proliferation and survival without the expected derepression of most retinoblastoma protein-controlled, E2F-responsive genes [3].

Biological context of Smarcb1

• Increased DNA damage sensitivity and apoptosis in cells lacking the Snf5/Ini1 subunit of the SWI/SNF chromatin remodeling complex [3].
• The gene encoding the SNF5/Ini1 core subunit of the SWI/SNF chromatin remodeling complex is a tumor suppressor in humans and mice, with an essential role in early embryonic development [3].
• All tumors examined showed loss of heterozygosity at the Ini1 locus [4].
• Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5 [5].

Anatomical context of Smarcb1

• Ini1-null embryos die between 3.5 and 5.5 days postcoitum, and Ini1-null blastocysts fail to hatch, form the trophectoderm, or expand the inner cell mass when cultured in vitro [6].
• Utilizing a reversibly inactivating conditional allele, we demonstrate that loss of Snf5/Ini1/Baf47/SmarcB1, a core subunit of SWI/SNF, results in highly penetrant cancer predisposition with 100% of mice developing mature CD8(+) T cell lymphoma or rare rhabdoid tumors with a median onset of only 11 weeks [5].

Other interactions of Smarcb1

• Although Ini1-null mice are embryonic lethal, 15-30% of mice heterozygous for Ini1 presented with poorly differentiated tumors with variable rhabdoid features [4].

Analytical, diagnostic and therapeutic context of Smarcb1

• Gene-targeting experiments confirmed that Ini1 also functions as a tumor suppressor in mice [4].

References