C. elegans ISWI and NURF301 antagonize an Rb-like pathway in the determination of multiple cell fates.
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.
Andersen
Erik C
EC
Howard Hughes Medical Institute, Department of Biology, Room 68-425, MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Lu
Xiaowei
X
Horvitz
H Robert
HR
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000033:anatomy & histology* / Q000196:embryology* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009024:Morphogenesis; D046912:Multiprotein Complexes; D010641:Phenotype; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; C437989:E(bx) protein, Drosophila; C086468:ISWI protein; D046912:Multiprotein Complexes; C513436:NURF-1 protein, C elegans; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; D018631:ras Proteins