Academic journal article Genetics

The LIN-15A and LIN-56 Transcriptional Regulators Interact to Negatively Regulate EGF/Ras Signaling in Caenorhabditis Elegans Vulval Cell-Fate Determination

Academic journal article Genetics

The LIN-15A and LIN-56 Transcriptional Regulators Interact to Negatively Regulate EGF/Ras Signaling in Caenorhabditis Elegans Vulval Cell-Fate Determination

Article excerpt

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^sub 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.

TUMORIGENESIS requires misregulation of pathways controlling cell proliferation, differentiation, and apoptosis and likely involves multiple mutations that result in the activation of proto-oncogenes and the inactivation of tumor-suppressor genes. A particularly frequent target of misregulation in human cancers is the epidermal growth factor (EGF) and Ras-signaling pathway that controls cell proliferation. The EGF/Ras pathway can be overactivated by misexpression of EGFlike ligands, mutation or overexpression of EGF receptors, or constitutivemutational activation of Ras (reviewed by Normanno et al. 2001, 2006; Downward 2003).

In Caenorhabditis elegans, an EGF/Ras pathway plays a central role in vulval development (reviewed by Kornfeld 1997; Moghal and Sternberg 2003). Six multipotent cells, P(3-8).p, of the ventral ectoderm each can express either the 1° or 2° vulval fates or the 3° nonvulval fate. The LIN-3 EGF ligand is expressed in the anchor cell of the somatic gonad and activates the LET-23 EGF receptor (EGFR) in the closest P(3-8).p cells. LET-23 EGFR subsequently signals through a Ras/MAP kinase pathway to specify vulval fates (Aroian et al. 1990; Han and Sternberg 1990; Hill and Sternberg 1992; Lackner et al. 1994; Kornfeld et al. 1995; Wu et al. 1995). P6.p assumes the 1° vulval fate, dividing three times to produce eight descendants, and P5.p and P7.p assume the 2° vulval fate, generating seven descendants each. The 22 progeny of P(5-7).p undergo morphogenesis to generate the adult vulva. P3.p, P4.p, and P8.p assume the nonvulval 3° fate and divide once and fuse with a multinucleate hypodermal cell, hyp7. Loss-offunction mutations in components of the EGF/Ras pathway cause P(5-7).p to adopt the nonvulval 3° fate and result in a vulvaless (Vul) phenotype. Gain-offunction mutations in let-23 EGFR or let-60 Ras or overexpression of lin-3 EGF cause P3.p, P4.p, and P8.p to adopt vulval 1° or 2° fates and result in a multivulva (Muv) phenotype (Beitel et al. 1990;Han and Sternberg 1990; Hill and Sternberg 1992; Katz et al. 1996). Muv animals produce extra vulval tissue that forms ectopic ventral protrusions.

The EGF/Ras pathway, which is essential for C. elegans vulval induction, is antagonized by the functionally redundant class A and B synthetic multivulva (synMuv) genes (Ferguson andHorvitz 1989). Hermaphrodites carrying only a single synMuv mutation generally appear as wild type for vulval induction, while hermaphrodites carrying mutations in both a class A and a class B synMuv gene exhibit a Muv phenotype. Four class A synMuv genes and at least 25 class B genes have been identified (Horvitz and Sulston 1980; Ferguson and Horvitz 1985, 1989; Lu and Horvitz 1998; Hsieh et al. 1999; Solari and Ahringer 2000; von Zelewsky et al. …

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