A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen
| Autor: | Daniel J Chiu, R. Mako Saito, Barbara Conradt, Laura D Young, Joseph E. Clayton, Nadin Memar, Sarah H. Roy, Eleanor M. Beltz, Jenna Holmen, Travis H Green, Isabella Lubin, David V. Tobin, Yuying Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cell division
Mutant Gene regulatory network Cell Cycle Proteins Biology Investigations ubiquitin-conjugating enzyme regulatory network 03 medical and health sciences 0302 clinical medicine RNA interference Genetics Animals Gene Regulatory Networks Cell Cycle Protein Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology Gene development intestine Ubiquitins Genetics (clinical) 030304 developmental biology 0303 health sciences Cell Cycle Gene Expression Regulation Developmental Cell cycle biology.organism_classification Cell biology C. elegans RNA Interference 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | G3: Genes|Genomes|Genetics |
| ISSN: | 2160-1836 |
| Popis: | The development and homeostasis of multicellular animals requires precise coordination of cell division and differentiation. We performed a genome-wide RNA interference screen in Caenorhabditis elegans to reveal the components of a regulatory network that promotes developmentally programmed cell-cycle quiescence. The 107 identified genes are predicted to constitute regulatory networks that are conserved among higher animals because almost half of the genes are represented by clear human orthologs. Using a series of mutant backgrounds to assess their genetic activities, the RNA interference clones displaying similar properties were clustered to establish potential regulatory relationships within the network. This approach uncovered four distinct genetic pathways controlling cell-cycle entry during intestinal organogenesis. The enhanced phenotypes observed for animals carrying compound mutations attest to the collaboration between distinct mechanisms to ensure strict developmental regulation of cell cycles. Moreover, we characterized ubc-25, a gene encoding an E2 ubiquitin-conjugating enzyme whose human ortholog, UBE2Q2, is deregulated in several cancers. Our genetic analyses suggested that ubc-25 acts in a linear pathway with cul-1/Cul1, in parallel to pathways employing cki-1/p27 and lin-35/pRb to promote cell-cycle quiescence. Further investigation of the potential regulatory mechanism demonstrated that ubc-25 activity negatively regulates CYE-1/cyclin E protein abundance in vivo. Together, our results show that the ubc-25-mediated pathway acts within a complex network that integrates the actions of multiple molecular mechanisms to control cell cycles during development. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|