ABSTRACT
The adenomatous polyposis coli (APC) tumor-suppressor protein, together with Axin and GSK3beta, forms a Wnt-regulated signaling complex that mediates phosphorylation-dependent degradation of beta-catenin by the proteasome. Siah-1, the human homolog of Drosophila seven in absentia, is a p53-inducible mediator of cell cycle arrest, tumor suppression, and apoptosis. We have now found that Siah-1 interacts with the carboxyl terminus of APC and promotes degradation of beta-catenin in mammalian cells. The ability of Siah-1 to downregulate beta-catenin signaling was also demonstrated by hypodorsalization of Xenopus embryos. Unexpectedly, degradation of beta-catenin by Siah-1 was independent of GSK3beta-mediated phosphorylation and did not require the F box protein beta-TrCP. These results indicate that APC and Siah-1 mediate a novel beta-catenin degradation pathway linking p53 activation to cell cycle control.
Subject(s)
Cytoskeletal Proteins/metabolism , Neoplasm Proteins/metabolism , Nuclear Proteins/pharmacology , Trans-Activators , Tumor Suppressor Protein p53/pharmacology , Xenopus Proteins , Adenomatous Polyposis Coli Protein , Animals , Calcium-Calmodulin-Dependent Protein Kinases/pharmacology , Cell Cycle/drug effects , Cytoskeletal Proteins/physiology , Embryo, Mammalian/abnormalities , Embryo, Mammalian/drug effects , Embryo, Nonmammalian , GTP-Binding Proteins/pharmacology , Glycogen Synthase Kinase 3 , Humans , Nuclear Proteins/metabolism , Phosphorylation/drug effects , Protein Binding , Signal Transduction/drug effects , Tumor Cells, Cultured , Ubiquitin-Protein Ligases , Xenopus , beta Catenin , beta-Transducin Repeat-Containing ProteinsABSTRACT
A 1355 bp sequence (accession number L32141) isolated from a gypsy moth (Lymantria dispar) cDNA library showed 68-74% sequence identity to mitochondrial large subunit ribosomal RNA (mt IrRNA) sequences of Locusta migratoria, Apis mellifera, Aedes albopictus, Anopheles gambiae and two Drosophila species. A comparison of the primary sequences of the mt IrRNAs from the above insects in four orders and from Esherichia coli demonstrated regions of conservation which presumably correspond to regions of functional and/or structural homology. A secondary structure for the gypsy moth mt IrRNA sequence was derived based on the proposed secondary structures of Drosophila yakuba and Aedes albopictus mt IrRNAs (Gutell & Fox, Nucleic Acid Res 16 (Suppl.), r175-r269, 1988). This sequence was found to hybridize to about 10-15% of the clones in several (eleven) gypsy moth cDNA libraries.
Subject(s)
DNA, Mitochondrial/genetics , Genes, Insect/genetics , Moths/genetics , RNA, Ribosomal/genetics , Animals , Base Sequence , DNA, Mitochondrial/chemistry , Molecular Sequence Data , Nucleic Acid Conformation , Sequence Homology, Nucleic AcidABSTRACT
In an effort to understand the forces shaping evolution of regulatory genes and patterns, we have compared data on interspecific differences in enzyme expression patterns among the rapidly evolving Hawaiian picture-winged Drosophila to similar data on the more conservative virilis species group. Divergence of regulatory patterns is significantly more common in the former group, but cause and effect are difficult to discern. Random fixation of regulatory variants in small populations and/or during speciation may be somewhat more likely than divergence driven by selection. Within the picture-winged group, we also have compared enzymes that fulfill different metabolic roles. There are highly significant differences between individual enzymes, but no obvious correlations to functional categories.
