SMARCA4

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SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
Protein SMARCA4 PDB 2grc.png
PDB rendering based on 2grc.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SMARCA4 ; BAF190; BAF190A; BRG1; MRD16; RTPS2; SNF2; SNF2L4; SNF2LB; SWI2; hSNF2b
External IDs OMIM603254 MGI88192 HomoloGene135927 GeneCards: SMARCA4 Gene
EC number 3.6.1.-
RNA expression pattern
PBB GE SMARCA4 208794 s at tn.png
PBB GE SMARCA4 208793 x at tn.png
PBB GE SMARCA4 213720 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6597 20586
Ensembl ENSG00000127616 ENSMUSG00000032187
UniProt P51532 Q3TKT4
RefSeq (mRNA) NM_001128844 NM_001174078
RefSeq (protein) NP_001122316 NP_001167549
Location (UCSC) Chr 19:
11.07 – 11.18 Mb
Chr 9:
21.62 – 21.7 Mb
PubMed search [1] [2]

Transcription activator BRG1 also known as ATP-dependent helicase SMARCA4 is a protein that in humans is encoded by the SMARCA4 gene.[1]

Function[edit]

The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44.[2]

BRG1 works to activate or repress transcription. Having functional BRG1 is important for development past the pre-implantation stage. Without having a functional BRG1, exhibited with knockout research, the embryo will not hatch out of the zona pellucida, which will inhibit implantation from occurring on the endometrium (uterine wall). BRG1 is also crucial to the development of sperm. During the first stages of meiosis in spermatogenesis there are high levels of BRG1. When BRG1 is genetically damaged, meiosis is stopped in prophase 1, hindering the development of sperm and would result in infertility. More knockout research has concluded BRG1’s aid in the development of smooth muscle. In a BRG1 knockout, smooth muscle in the gastrointestinal tract lacks contractility, and intestines are incomplete in some cases. Another defect occurring in knocking out BRG1 in smooth muscle development is heart complications such as an open ductus arteriosus after birth.[3][4]

Clinical significance[edit]

Mutations in this gene were first recognized in human lung cancer cell lines.[5] Later it was recognized that mutations exist in a significant frequency of medulloblastoma and pancreatic cancers among other tumor subtypes.[6][7][8] Mutations in BRG1 (or SMARCA4) appear to be mutually exclusive with the presence of activation at any of the MYC-genes, which indicates that the BRG1 and MYC proteins are functionally related.[5][9] Another recent study demonstrated a causal role of BRG1 in the control of retinoic acid and glucocorticoid-induced cell differentiation in lung cancer and in other tumor types. This enables the cancer cell to sustain undifferentiated gene expression programs that affect the control of key cellular processes. Furthermore, it explains why lung cancer and other solid tumors are completely refractory to treatments based on these compounds that are effective therapies for some types of leukemia.[10] The role of BRG1 in sensitivity or resistance to anti-cancer drugs had been recently highlighted by the elucidation of the mechanisms of action of darinaparsin, an arsenic-based anti-cancer drugs. Darinaparsin has been shown to induce phosphorylation of BRG1, which leads to its exclusion from the chromatin. When excluded from the chromatin, BRG1 can no longer act as a transcriptional co-regulator. This leads to the inability of cells to express HO-1, a cytoprotective enzyme.[11]

Interactions[edit]

SMARCA4 has been shown to interact with:


References[edit]

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  2. ^ "Entrez Gene: SMARCA4 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4". 
  3. ^ Kim Y, Fedoriw AM, Magnuson T (March 2012). "An essential role for a mammalian SWI/SNF chromatin-remodeling complex during male meiosis". Development 139 (6): 1133–40. doi:10.1242/dev.073478. PMC 3283123. PMID 22318225. 
  4. ^ Zhang M, Chen M, Kim JR, Zhou J, Jones RE, Tune JD, Kassab GS, Metzger D, Ahlfeld S, Conway SJ, Herring BP (July 2011). "SWI/SNF complexes containing Brahma or Brahma-related gene 1 play distinct roles in smooth muscle development". Mol. Cell. Biol. 31 (13): 2618–31. doi:10.1128/MCB.01338-10. PMC 3133369. PMID 21518954. 
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  6. ^ Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, et al. (2012). "Dissecting the genomic complexity underlying medulloblastoma". Nature 488 (7409): 100–5. doi:10.1038/nature11284. PMC 3662966. PMID 22832583. 
  7. ^ Shain AH, Giacomini CP, Matsukuma K, Karikari CA, Bashyam MD, Hidalgo M, Maitra A, Pollack JR (2012). "Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer". Proc. Natl. Acad. Sci. U.S.A. 109 (5): E252–9. doi:10.1073/pnas.1114817109. PMC 3277150. PMID 22233809. 
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  23. ^ Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E (1999). "Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest". Mol. Cell. Biol. 19 (2): 1460–9. PMC 116074. PMID 9891079. 
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Further reading[edit]

External links[edit]