Disease relevance of SMARCB1

• The SMARCB1/INI1 gene encodes for an invariant subunit of SWI/SNF chromatin remodeling complex and has been previously reported to act as a tumor suppressor gene frequently inactivated in infantile malignant rhabdoid tumors [1].
• Overall, these results point to SMARCB1/INI1 gene involvement in the genesis and/or progression of epithelioid sarcomas [1].
• We found a nucleotide change at codon 152 of SMARCB1 that may alter the amount of immunoprecipitated cMYC protein, but we finally determined that SMARCB1 is highly conserved in human solid carcinomas [2].
• We carried out a search for mutations in SMARCB1 in 60 human gastro-intestinal tract carcinoma cases, 122 breast cancer cases, and 36 human cancer cell lines [2].
• Meningiomas and schwannomas are tumors frequently deleting various regions on chromosome 22, including the SMARCB1 locus [3].
• All four schwannomas displayed complete loss of nuclear INI1 protein expression in part of the cells [4].
• The results from the genome-wide single nucleotide polymorphism array analysis suggest that INI1 is the primary tumor suppressor gene involved in the development of rhabdoid tumors with no second locus identified [5].

High impact information on SMARCB1

• c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function [6].
• Our results suggest that the SWI/SNF complex is necessary for c-MYC-mediated transactivation and that the c-MYC-INI1 interaction helps recruit the complex [6].
• Our results indicate that Ini1/hSNF5 is required for the efficient replication of papillomavirus DNA and is therefore needed, either alone or in complex with SWI/SNF complex, for mammalian DNA replication as well [7].
• We analysed the sequence of hSNF5/INI1 and found frameshift or nonsense mutations of this gene in six other cell lines [8].
• The hSNF5 subunit of human SWI/SNF ATP-dependent chromatin remodeling complexes is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs) [9].

Chemical compound and disease context of SMARCB1

• The finding that the two repeat motifs of Ini1 display differential binding to HIV-1 IN and that this discrete component of mammalian SWI/SNF complex binds to DNA will help understand the role of Ini1 in HIV-1 integration and in cellular process [10].
• We have developed a tetracycline-based hSNF5/INI1-inducible system in a hSNF5/INI1-deficient malignant rhabdoid tumor cell line and studied time course variation of 22,000 genes/expressed sequence tags upon hSNF5/INI1 induction [11].
• Following hSNF5 expression, we observed transcriptional activation of the tumor suppressor p16(INK4a) but not of p14(ARF), repression of several cyclins and CD44, a cell surface glycoprotein implicated in metastasis [12].
• In this paper we propose the accurate liquid chromatographic determination of glycolate in blood and dialysate as a means to detect type I primary hyperoxaluria in patients on maintenance hemodialysis (RDT) [13].
• Systemic oxalosis is a constant feature in patients with primary hyperoxaluria type 1 (PH1) and chronic renal failure (CRF) and is not prevented by regular dialysis (RDT), because removal cannot keep up with retention and overproduction of oxalate [14].

Biological context of SMARCB1

• SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas [1].
• A single-nucleotide polymorphism of SMARCB1 in human breast cancers [2].
• Codons 152 and 299 of SMARCB1 are localized near or within the binding site for the cMYC protein [2].
• We therefore directly sequenced seven SMARCB1 exons (90% of the open reading frame) in search for mutations in 41 meningiomas and 23 schwannomas [3].
• INI1hSNF5 (HUGO symbol: SMARCB1), located at 22q11, encodes a component of the ATP-dependent chromatin remodeling hSWI-SNF complex; it is a tumor suppressor gene that is mutated in several malignant tumors [15].

Anatomical context of SMARCB1

• In humans, the gene encoding the BAF47/hSNF5 subunit of the complex, located at 22q11.2, has been found to be mutated in a number of human tumors including rhabdoid, rhabdomyosarcoma, chronic myeloid leukemia, and CNS tumors such as medulloblastomas and choroid plexus carcinomas [16].
• Interindividual variation in the frequencies of various splice forms in CD4 T cells from blood donors was observed for INI1 [17].
• These results suggest that hSNF5 loss is not equivalent to BRG1/BRM loss in human tumor cell lines [18].
• Central nervous system and peripheral RTs have been associated with biallelic inactivation of the hSNF5/INI1/SMARCB1 (hSNF5/INI1) tumour suppressor gene [19].
• Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors [20].

Associations of SMARCB1 with chemical compounds

• In two of the three ini1-deficient cell lines, apoptosis was found to occur after the infection, as detected by the presence of cleaved poly (ADP-ribose) polymerase [21].
• We employed bisulfite modification, polymerase chain reaction, and sequence analysis to determine the methylation status of the cytosine nucleotides in the predicted promoter region of the INI1 gene, and two GC repeat regions in intron 1 [22].
• The aim of this study was to determine whether hypermethylation or mutation of the 5' promoter region of INI1, or hypermethylation of CpG dinucleotides in a GC-rich repeat region within the first intron, could account for the decreased expression of INI1 observed in these tumors [22].
• In order to examine its potential role in the pathogenesis of choroid plexus tumours, we analysed exons 1-9 of hSNF5/INI1 by SSCP analysis in a series of 21 formalin-fixed and paraffin-embedded CPP [23].
• In CRF, Cltot of tryptophan and histidine was elevated and Cltot of phenylalanine was reduced; in RDT, Cltot of histidine, methionine, tryptophan, lysine, isoleucine, and leucine was raised [24].

Physical interactions of SMARCB1

• A search for INI1-interacting proteins using the two-hybrid system led to the isolation of c-MYC, a transactivator [6].
• In the present report, we demonstrate that hSNF5/INI1 binds to GADD34 in part through the PP1 docking site within a domain homologous to herpes simplex virus-1 ICP34 [25].
• We provide functional evidence that SMARCB1 is involved in prednisolone resistance and identified a promoter SNP that alters the level of SMARCB1 mRNA and protein expression and the binding of PARP1 to the SMARCB1 promoter [26].

Regulatory relationships of SMARCB1

• Ini1/hSNF5 is dispensable for retrovirus-induced cytoplasmic accumulation of PML and does not interfere with integration [27].
• Instead, p21CIP/WAF1 remained activated by hSNF5 in the absence of high p16INK4a expression, apparently causing the growth arrest in A204 [28].
• In summary, our studies suggest that hSNF5 loss may influence the regulation of multiple CDK inhibitors involved in replicative senescence [28].
• These observations demonstrate that INI1 has a masked NES that mediates regulated hCRM1/exportin1-dependent nuclear export and we propose that mutations that cause deregulated nuclear export of the protein could lead to tumorigenesis [29].
• Chromatin immunoprecipitations indicated that hSNF5 activates p16(INK4a) transcription and CD44 down-regulation by mediating recruitment of the SWI/SNF complex [12].

Other interactions of SMARCB1

• The c-MYC-INI1 interaction was observed both in vitro and in vivo [6].
• Thus in human cells, SWI/SNF enzyme complex formation and the expression of many BRG1-dependent genes are independent of INI1 [30].
• Chromatin immunoprecipitation experiments revealed that BRG1 inducibly binds to the CIITA promoter despite the absence of INI1 [30].
• While PML was shown to counteract proviral establishment, it remained unclear whether Ini1, a protein implicated in various processes during human immunodeficiency virus replication, has the same potential [27].
• Establishment of a cell line from a malignant rhabdoid tumor of the liver lacking the function of two tumor suppressor genes, hSNF5/INI1 and p16 [31].

Analytical, diagnostic and therapeutic context of SMARCB1

• We confirmed and further extended the number of cases with SMARCB1/INI1 inactivation to 6 of 11 cases, by real-time quantitative PCR analysis of mRNA expression and by SMARCB1/INI1 immunohistochemistry [1].
• Immunoprecipitation assays identified viral proteins IN, Vpr, MA, and cellular Ini1 and PML associated with both cRTCs and nRTCs, whereas CA was detected only in cRTCs and RT was diminished in nRTCs [32].
• Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion [33].
• Immunohistochemistry to assess expression of SMARCB1/INI1 may be useful in the diagnosis of rhabdoid tumors of the CNS, kidneys and soft tissue.Modern Pathology (2006) 19, 717-725. doi:10.1038/modpathol.3800581; published online 10 March 2006 [34].
• Genetic alterations of the SNF5/INI1/SMARCB1 gene were investigated by PCR-single-strand conformation polymorphism (SSCP), loss of heterozygosity (LOH), sequence, and karyotyping analyses, and the gene expression level was determined by real-time quantitative RT-PCR analysis [35].

References