• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Dec 1, 1998; 17(23): 6979–6991.
PMCID: PMC1171046

Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha).

Abstract

The mammalian SWI-SNF complex is an evolutionarily conserved, multi-subunit machine, involved in chromatin remodelling during transcriptional activation. Within this complex, the BRM (SNF2alpha) and BRG1 (SNF2beta) proteins are mutually exclusive subunits that are believed to affect nucleosomal structures using the energy of ATP hydrolysis. In order to characterize possible differences in the function of BRM and BRG1, and to gain further insights into the role of BRM-containing SWI-SNF complexes, the mouse BRM gene was inactivated by homologous recombination. BRM-/- mice develop normally, suggesting that an observed up-regulation of the BRG1 protein can functionally replace BRM in the SWI-SNF complexes of mutant cells. Nonetheless, adult mutant mice were approximately 15% heavier than control littermates. This may be caused by increased cell proliferation, as demonstrated by a higher mitotic index detected in mutant livers. This is supported further by the observation that mutant embryonic fibroblasts were significantly deficient in their ability to arrest in the G0/G1 phase of the cell cycle in response to cell confluency or DNA damage. These studies suggest that BRM participates in the regulation of cell proliferation in adult mice.

Full Text

The Full Text of this article is available as a PDF (685K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Almasan A, Yin Y, Kelly RE, Lee EY, Bradley A, Li W, Bertino JR, Wahl GM. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5436–5440. [PMC free article] [PubMed]
  • Burns LG, Peterson CL. Protein complexes for remodeling chromatin. Biochim Biophys Acta. 1997 Feb 7;1350(2):159–168. [PubMed]
  • Burns LG, Peterson CL. The yeast SWI-SNF complex facilitates binding of a transcriptional activator to nucleosomal sites in vivo. Mol Cell Biol. 1997 Aug;17(8):4811–4819. [PMC free article] [PubMed]
  • Carlson M, Laurent BC. The SNF/SWI family of global transcriptional activators. Curr Opin Cell Biol. 1994 Jun;6(3):396–402. [PubMed]
  • Chiba H, Muramatsu M, Nomoto A, Kato H. Two human homologues of Saccharomyces cerevisiae SWI2/SNF2 and Drosophila brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor. Nucleic Acids Res. 1994 May 25;22(10):1815–1820. [PMC free article] [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schütz G. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 1995 Jul 1;9(13):1608–1621. [PubMed]
  • Colucci-Guyon E, Portier MM, Dunia I, Paulin D, Pournin S, Babinet C. Mice lacking vimentin develop and reproduce without an obvious phenotype. Cell. 1994 Nov 18;79(4):679–694. [PubMed]
  • Côté J, Quinn J, Workman JL, Peterson CL. Stimulation of GAL4 derivative binding to nucleosomal DNA by the yeast SWI/SNF complex. Science. 1994 Jul 1;265(5168):53–60. [PubMed]
  • Deng C, Zhang P, Harper JW, Elledge SJ, Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 1995 Aug 25;82(4):675–684. [PubMed]
  • Dunaief JL, Strober BE, Guha S, Khavari PA, Alin K, Luban J, Begemann M, Crabtree GR, Goff SP. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell. 1994 Oct 7;79(1):119–130. [PubMed]
  • Elfring LK, Daniel C, Papoulas O, Deuring R, Sarte M, Moseley S, Beek SJ, Waldrip WR, Daubresse G, DePace A, et al. Genetic analysis of brahma: the Drosophila homolog of the yeast chromatin remodeling factor SWI2/SNF2. Genetics. 1998 Jan;148(1):251–265. [PMC free article] [PubMed]
  • Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 1995 Oct 1;9(19):2364–2372. [PubMed]
  • Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell. 1996 May 31;85(5):733–744. [PubMed]
  • Hirschhorn JN, Brown SA, Clark CD, Winston F. Evidence that SNF2/SWI2 and SNF5 activate transcription in yeast by altering chromatin structure. Genes Dev. 1992 Dec;6(12A):2288–2298. [PubMed]
  • Imbalzano AN, Kwon H, Green MR, Kingston RE. Facilitated binding of TATA-binding protein to nucleosomal DNA. Nature. 1994 Aug 11;370(6489):481–485. [PubMed]
  • Jeon SH, Kang MG, Kim YH, Jin YH, Lee C, Chung HY, Kwon H, Park SD, Seong RH. A new mouse gene, SRG3, related to the SWI3 of Saccharomyces cerevisiae, is required for apoptosis induced by glucocorticoids in a thymoma cell line. J Exp Med. 1997 May 19;185(10):1827–1836. [PMC free article] [PubMed]
  • Kadonaga JT. Eukaryotic transcription: an interlaced network of transcription factors and chromatin-modifying machines. Cell. 1998 Feb 6;92(3):307–313. [PubMed]
  • Kalpana GV, Marmon S, Wang W, Crabtree GR, Goff SP. Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. Science. 1994 Dec 23;266(5193):2002–2006. [PubMed]
  • Kennison JA. The Polycomb and trithorax group proteins of Drosophila: trans-regulators of homeotic gene function. Annu Rev Genet. 1995;29:289–303. [PubMed]
  • Kennison JA, Tamkun JW. Dosage-dependent modifiers of polycomb and antennapedia mutations in Drosophila. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8136–8140. [PMC free article] [PubMed]
  • Khavari PA, Peterson CL, Tamkun JW, Mendel DB, Crabtree GR. BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature. 1993 Nov 11;366(6451):170–174. [PubMed]
  • Kingston RE, Bunker CA, Imbalzano AN. Repression and activation by multiprotein complexes that alter chromatin structure. Genes Dev. 1996 Apr 15;10(8):905–920. [PubMed]
  • Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell. 1996 May 31;85(5):721–732. [PubMed]
  • Koff A, Polyak K. p27KIP1, an inhibitor of cyclin-dependent kinases. Prog Cell Cycle Res. 1995;1:141–147. [PubMed]
  • Kwon H, Imbalzano AN, Khavari PA, Kingston RE, Green MR. Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature. 1994 Aug 11;370(6489):477–481. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • LeGouy E, Thompson EM, Muchardt C, Renard JP. Differential preimplantation regulation of two mouse homologues of the yeast SWI2 protein. Dev Dyn. 1998 May;212(1):38–48. [PubMed]
  • Luo RX, Postigo AA, Dean DC. Rb interacts with histone deacetylase to repress transcription. Cell. 1998 Feb 20;92(4):463–473. [PubMed]
  • Muchardt C, Yaniv M. A human homologue of Saccharomyces cerevisiae SNF2/SWI2 and Drosophila brm genes potentiates transcriptional activation by the glucocorticoid receptor. EMBO J. 1993 Nov;12(11):4279–4290. [PMC free article] [PubMed]
  • Muchardt C, Sardet C, Bourachot B, Onufryk C, Yaniv M. A human protein with homology to Saccharomyces cerevisiae SNF5 interacts with the potential helicase hbrm. Nucleic Acids Res. 1995 Apr 11;23(7):1127–1132. [PMC free article] [PubMed]
  • Muchardt C, Reyes JC, Bourachot B, Leguoy E, Yaniv M. The hbrm and BRG-1 proteins, components of the human SNF/SWI complex, are phosphorylated and excluded from the condensed chromosomes during mitosis. EMBO J. 1996 Jul 1;15(13):3394–3402. [PMC free article] [PubMed]
  • Muchardt C, Bourachot B, Reyes JC, Yaniv M. ras transformation is associated with decreased expression of the brm/SNF2alpha ATPase from the mammalian SWI-SNF complex. EMBO J. 1998 Jan 2;17(1):223–231. [PMC free article] [PubMed]
  • Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama K. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 1996 May 31;85(5):707–720. [PubMed]
  • Pazin MJ, Kadonaga JT. SWI2/SNF2 and related proteins: ATP-driven motors that disrupt protein-DNA interactions? Cell. 1997 Mar 21;88(6):737–740. [PubMed]
  • Pazin MJ, Kadonaga JT. What's up and down with histone deacetylation and transcription? Cell. 1997 May 2;89(3):325–328. [PubMed]
  • Peterson CL, Herskowitz I. Characterization of the yeast SWI1, SWI2, and SWI3 genes, which encode a global activator of transcription. Cell. 1992 Feb 7;68(3):573–583. [PubMed]
  • Peterson CL, Tamkun JW. The SWI-SNF complex: a chromatin remodeling machine? Trends Biochem Sci. 1995 Apr;20(4):143–146. [PubMed]
  • Pirrotta V. PcG complexes and chromatin silencing. Curr Opin Genet Dev. 1997 Apr;7(2):249–258. [PubMed]
  • Pontoglio M, Faust DM, Doyen A, Yaniv M, Weiss MC. Hepatocyte nuclear factor 1alpha gene inactivation impairs chromatin remodeling and demethylation of the phenylalanine hydroxylase gene. Mol Cell Biol. 1997 Sep;17(9):4948–4956. [PMC free article] [PubMed]
  • Qin XQ, Livingston DM, Kaelin WG, Jr, Adams PD. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10918–10922. [PMC free article] [PubMed]
  • Randazzo FM, Khavari P, Crabtree G, Tamkun J, Rossant J. brg1: a putative murine homologue of the Drosophila brahma gene, a homeotic gene regulator. Dev Biol. 1994 Jan;161(1):229–242. [PubMed]
  • Reyes JC, Muchardt C, Yaniv M. Components of the human SWI/SNF complex are enriched in active chromatin and are associated with the nuclear matrix. J Cell Biol. 1997 Apr 21;137(2):263–274. [PMC free article] [PubMed]
  • Schnitzler G, Sif S, Kingston RE. Human SWI/SNF interconverts a nucleosome between its base state and a stable remodeled state. Cell. 1998 Jul 10;94(1):17–27. [PubMed]
  • Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996 Apr 5;85(1):27–37. [PubMed]
  • Sherr CJ. Cancer cell cycles. Science. 1996 Dec 6;274(5293):1672–1677. [PubMed]
  • Singh P, Coe J, Hong W. A role for retinoblastoma protein in potentiating transcriptional activation by the glucocorticoid receptor. Nature. 1995 Apr 6;374(6522):562–565. [PubMed]
  • Strober BE, Dunaief JL, Guha, Goff SP. Functional interactions between the hBRM/hBRG1 transcriptional activators and the pRB family of proteins. Mol Cell Biol. 1996 Apr;16(4):1576–1583. [PMC free article] [PubMed]
  • Sumi-Ichinose C, Ichinose H, Metzger D, Chambon P. SNF2beta-BRG1 is essential for the viability of F9 murine embryonal carcinoma cells. Mol Cell Biol. 1997 Oct;17(10):5976–5986. [PMC free article] [PubMed]
  • Tamkun JW, Deuring R, Scott MP, Kissinger M, Pattatucci AM, Kaufman TC, Kennison JA. brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell. 1992 Feb 7;68(3):561–572. [PubMed]
  • Treich I, Cairns BR, de los Santos T, Brewster E, Carlson M. SNF11, a new component of the yeast SNF-SWI complex that interacts with a conserved region of SNF2. Mol Cell Biol. 1995 Aug;15(8):4240–4248. [PMC free article] [PubMed]
  • Trouche D, Le Chalony C, Muchardt C, Yaniv M, Kouzarides T. RB and hbrm cooperate to repress the activation functions of E2F1. Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11268–11273. [PMC free article] [PubMed]
  • Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991 Jun 28;65(7):1153–1163. [PubMed]
  • van Lohuizen M. Functional analysis of mouse Polycomb group genes. Cell Mol Life Sci. 1998 Jan;54(1):71–79. [PubMed]
  • Versteege I, Sévenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998 Jul 9;394(6689):203–206. [PubMed]
  • Wang W, Côté J, Xue Y, Zhou S, Khavari PA, Biggar SR, Muchardt C, Kalpana GV, Goff SP, Yaniv M, et al. Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 1996 Oct 1;15(19):5370–5382. [PMC free article] [PubMed]
  • Wang W, Xue Y, Zhou S, Kuo A, Cairns BR, Crabtree GR. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 1996 Sep 1;10(17):2117–2130. [PubMed]
  • Wang W, Chi T, Xue Y, Zhou S, Kuo A, Crabtree GR. Architectural DNA binding by a high-mobility-group/kinesin-like subunit in mammalian SWI/SNF-related complexes. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):492–498. [PMC free article] [PubMed]
  • Wolffe AP, Wong J, Pruss D. Activators and repressors: making use of chromatin to regulate transcription. Genes Cells. 1997 May;2(5):291–302. [PubMed]
  • Wu X, Levine AJ. p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3602–3606. [PMC free article] [PubMed]
  • Yoshinaga SK, Peterson CL, Herskowitz I, Yamamoto KR. Roles of SWI1, SWI2, and SWI3 proteins for transcriptional enhancement by steroid receptors. Science. 1992 Dec 4;258(5088):1598–1604. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • BioAssay
    BioAssay
    PubChem BioAssay links
  • Gene
    Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • Nucleotide
    Nucleotide
    Published Nucleotide sequences
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Protein
    Published protein sequences
  • PubMed
    PubMed
    PubMed citations for these articles