C. elegans ISWI and NURF301 antagonize an Rb-like pathway in the determination of multiple cell fates

Development. 2006 Jul;133(14):2695-704. doi: 10.1242/dev.02444. Epub 2006 Jun 14.

Abstract

The class A, B and C synthetic multivulva (synMuv) genes act redundantly to negatively regulate the expression of vulval cell fates in Caenorhabditis elegans. The class B and C synMuv proteins include homologs of proteins that modulate chromatin and influence transcription in other organisms similar to members of the Myb-MuvB/dREAM, NuRD and Tip60/NuA4 complexes. To determine how these chromatin-remodeling activities negatively regulate the vulval cell-fate decision, we isolated a suppressor of the synMuv phenotype and found that the suppressor gene encodes the C. elegans homolog of Drosophila melanogaster ISWI. The C. elegans ISW-1 protein likely acts as part of a Nucleosome Remodeling Factor (NURF) complex with NURF-1, a nematode ortholog of NURF301, to promote the synMuv phenotype. isw-1 and nurf-1 mutations suppress both the synMuv phenotype and the multivulva phenotype caused by overactivation of the Ras pathway. Our data suggest that a NURF-like complex promotes the expression of vulval cell fates by antagonizing the transcriptional and chromatin-remodeling activities of complexes similar to Myb-MuvB/dREAM, NuRD and Tip60/NuA4. Because the phenotypes caused by a null mutation in the tumor-suppressor and class B synMuv gene lin-35 Rb and a gain-of-function mutation in let-60 Ras are suppressed by reduction of isw-1 function, NURF complex proteins might be effective targets for cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Caenorhabditis elegans / anatomy & histology*
  • Caenorhabditis elegans / embryology*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Lineage
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Humans
  • Morphogenesis*
  • Multiprotein Complexes
  • Phenotype
  • RNA Interference
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism*
  • Signal Transduction / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Drosophila Proteins
  • E(bx) protein, Drosophila
  • ISWI protein
  • Multiprotein Complexes
  • NURF-1 protein, C elegans
  • Retinoblastoma Protein
  • Transcription Factors
  • Adenosine Triphosphatases
  • ras Proteins