The LIN-15A and LIN-56 Transcriptional Regulators Interact to Negatively Regulate EGF/Ras Signaling inCaenorhabditis elegansVulval Cell-Fate Determination

Abstract

The restricted expression of epidermal growth factor (EGF) family ligands is important for proper development and for preventing cancerous growth in mammals. In Caenorhabditis elegans, the class A and B synthetic multivulva (synMuv) genes redundantly repress expression of lin-3 EGF to negatively regulate Ras-mediated vulval development. The class B synMuv genes encode proteins homologous to components of the NuRD and Myb-MuvB/dREAM transcriptional repressor complexes, indicating that they likely silence lin-3 EGF through chromatin remodeling. The two class A synMuv genes cloned thus far, lin-8 and lin-15A, both encode novel proteins. The LIN-8 protein is nuclear. We have characterized the class A synMuv gene lin-56 and found it to encode a novel protein that shares a THAP-like C 2 CH motif with LIN-15A. Both the LIN-56 and LIN-15A proteins localize to nuclei. Wild-type levels of LIN-56 require LIN-15A, and wild-type levels and/or localization of LIN-15A requires LIN-56. Furthermore, LIN-56 and LIN-15A interact in the yeast two-hybrid system. We propose that LIN-56 and LIN-15A associate in a nuclear complex that inhibits vulval specification by repressing lin-3 EGF expression.

Restriction of Cellular Plasticity of Differentiated Cells Mediated by Chromatin Modifiers, Transcription Factors and Protein Kinases

“…SynMuv mutants in each class correspond to groups of interacting genes, and of the two major classes, the SynMuvB class contains homologs of DP, E2F, and Rb, several of which have been suggested to form various transcriptionally repressive complexes, including the DRM/DREAM and NuRD complexes (Fay and Yochem 2007). SynMuvA class genes, however, which include lin-15A , lin-8 , lin-38 and lin-56 , encode novel nuclear proteins with no non-nematode orthologs (Davison et al 2005; Fay and Yochem 2007; Davison et al 2011). LIN-8 has been shown to physically interact with the LIN-35/Rb transcriptional repressor (a SynMuvB gene)(Davison et al 2005).…”

The Caenorhabditis elegans Synthetic Multivulva Genes Prevent Ras Pathway Activation by Tightly Repressing Global Ectopic Expression of lin-3 EGF

“…For example, the class B synMuv genes encode a DP/E2F/Rb complex [16] , [17] , a nucleosome remodeling and deacteylase (NuRD) complex [18] , [19] , two histone methyltransferases [20] , [21] and a heterochromatin protein 1 homolog [22] . Of the three molecularly-characterized class A synMuv genes, two encode proteins with a zinc-finger-like THAP domain [23] – [25] . The expression patterns of three class A synMuv proteins have been studied, and all three are localized to the nucleus, suggesting that class A synMuv proteins regulate transcription [25] , [26] .…”

The Signaling Network Controlling C. elegans Vulval Cell Fate Patterning

“…Accordingly, many synMuv genes encode transcriptional and/or epigenetic regulators (reviewed in [131]). For example, some synMuv A group genes encode proteins that contain a zinc-finger-like THAP domain [132,133,134]. The synMuv B group genes have homology with mammalian proteins that are involved in chromatin remodeling, transcription repression, and histone modification [135,136,137,138,139,140,141].…”