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The dispatched (disp) gene is required for long-range Hedgehog (Hh) signaling in Drosophila. Here, we demonstrate that one of two murine homologs, mDispA, can rescue disp function in Drosophila and is essential for all Hh patterning activities examined in the early mouse embryo. Embryonic fibroblasts lacking mDispA respond normally to exogenously provided Sonic hedgehog (Shh) signal, but are impaired...
Ribosome recycling factor (RRF) disassembles posttermination complexes in conjunction with elongation factor EF-G, liberating ribosomes for further rounds of translation. The striking resemblance of its L-shaped structure to that of tRNA has suggested that the mode of action of RRF may be based on mimicry of tRNA. Directed hydroxyl radical probing of 16S and 23S rRNA from Fe(II) tethered to ten positions...
A pharmacological screen identified the H + and K + ATPase transporter as obligatory for normal orientation of the left-right body axis in Xenopus. Maternal H + /K + -ATPase mRNA is symmetrically expressed in the 1-cell Xenopus embryo but becomes localized during the first two cell divisions, demonstrating that asymmetry is generated within two hours postfertilization...
Protein lysine methylation by SET domain enzymes regulates chromatin structure, gene silencing, transcriptional activation, plant metabolism, and other processes. The 2.6 Å resolution structure of Rubisco large subunit methyltransferase in a pseudo-bisubstrate complex with S-adenosylhomocysteine and a HEPES ion reveals an all-β architecture for the SET domain embedded within a larger α-helical enzyme...
AdoMet-dependent methylation of histones is part of the ''histone code'' that can profoundly influence gene expression. We describe the crystal structure of Neurospora DIM-5, a histone H3 lysine 9 methyltranferase (HKMT), determined at 1.98 Å resolution, as well as results of biochemical characterization and site-directed mutagenesis of key residues. This SET domain protein bears no structural similarity...
Methylation of lysine residues in the N-terminal tails of histones is thought to represent an important component of the mechanism that regulates chromatin structure. The evolutionarily conserved SET domain occurs in most proteins known to possess histone lysine methyltransferase activity. We present here the crystal structure of a large fragment of human SET7/9 that contains a N-terminal β-sheet...
PAS kinase is a serine/threonine kinase regulated in cis by a PAS domain. A genetic study of the two PAS kinase genes in budding yeast gave evidence of the involvement of these enzymes in the control of sugar metabolism and translation. Using a biochemical screen for PAS kinase substrates, three translation factors were identified as direct phosphorylation targets. PAS kinase was also found to phosphorylate...
The therapeutic value of DNA-damaging antineoplastic agents is dependent upon their ability to induce tumor cell apoptosis while sparing most normal tissues. Here, we show that a component of the apoptotic response to these agents in several different types of tumor cells is the deamidation of two asparagines in the unstructured loop of Bcl-x L , and we demonstrate that deamidation of these...
We have utilized in vitro three-dimensional epithelial cell cultures to analyze the role of apoptosis in the formation and maintenance of a hollow glandular architecture. Lumen formation is associated with the selective apoptosis of centrally located cells; this apoptosis follows apicobasal polarization and precedes proliferative suppression during acinar development. Notably, either inhibiting apoptosis...
Proteins bearing the widely distributed SET domain have been shown to methylate lysine residues in histones and other proteins. In this issue, three-dimensional structures are reported for three very different SET domain-containing proteins. The structures reveal novel folds for several new domains, including SET, and provide early insights into mechanisms of catalysis and molecular recognition in...
This year, the recipients of the Lasker Award for Basic Medical Research are James Rothman and Randy Schekman. This highly anticipated honor highlights their unique contributions to our understanding of the mechanisms of membrane traffic.
The Period2 gene plays a key role in controlling circadian rhythm in mice. We report here that mice deficient in the mPer2 gene are cancer prone. After γ radiation, these mice show a marked increase in tumor development and reduced apoptosis in thymocytes. The core circadian genes are induced by γ radiation in wild-type mice but not in mPer2 mutant mice. Temporal expression of genes involved in cell...
The Target of Rapamycin (TOR) proteins function in signaling pathways that promote protein synthesis and cell growth. In yeast, TOR signaling is regulated by nutrient availability, whereas in metazoan cells TOR activities may be controlled by both nutrients and growth factors. The recent identification of novel TOR-interacting proteins has provided crucial insights into TOR regulation and function.
Comparative sequence analyses of eukaryotic genes and genomic regions are beginning to provide a wealth of information that is directly relevant to human biology. Functional changes that set us apart from apes are identifiable, as are functional constraints in proteins and genomic elements that arose in our relatively distant phylogenetic past.
When a nascent vesicle buds, the membrane must curve. Several mechanisms have been proposed for curvature creation or stabilization. Structural analysis of the ENTH domain of the endocytic protein epsin has suggested a new mechanism, in which the ENTH domain pushes its way into membranes, thus bending them into shape.
Apoptosis-inducing factor (AIF) was originally discovered as a mitochondrial protein that, like cytochrome c, is released into the cytoplasm during cell death. New evidence suggests, however, that a redox-active enzymatic region of AIF may be antiapoptotic while a DNA binding region is proapoptotic.
In the small intestine, the progeny of stem cells migrate in precise patterns. Absorptive, enteroendocrine, and goblet cells migrate toward the villus while Paneth cells occupy the bottom of the crypts. We show here that β-catenin and TCF inversely control the expression of the EphB2/EphB3 receptors and their ligand ephrin-B1 in colorectal cancer and along the crypt-villus axis. Disruption of EphB2...
Polycomb group (PcG) proteins maintain transcriptional repression during development, likely by creating repressive chromatin states. The Extra Sex Combs (ESC) and Enhancer of Zeste [E(Z)] proteins are partners in an essential PcG complex, but its full composition and biochemical activities are not known. A SET domain in E(Z) suggests this complex might methylate histones. We purified an ESC-E(Z)...
The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of β-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is...
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