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Transcription start site selection in eukaryotes is mediated through combinations of the TATA, initiator (Inr), and downstream promoter elements (DPE). In Trichomonas vaginalis, a parabasalian flagellate thought to represent an ancient eukaryote lineage, the Inr appears to be solely responsible for start site selection and is recognized by the initiator binding protein 39 kDa (IBP39). IBP39 contains...
The structure of the initiator binding protein from the primitive eukaryote Trichomonas vaginalis reveals how a single protein can orchestrate promoter recognition, RNA polymerase II recruitment, and start site selection, and provides an evolutionary link with transcription initiation in higher eukaryotes.
In C. elegans, the transcription factor DAF-16 promotes longevity in response to reduced insulin/IGF-1 signaling or germline ablation. In this study, we have asked how different tissues interact to specify the lifespan of the animal. We find that several tissues act as signaling centers. In particular, DAF-16 activity in the intestine, which is also the animal's adipose tissue, completely restores...
Plants, compared to animals, exhibit an amazing adaptability and plasticity in their development. This is largely dependent on the ability of plants to form new organs, such as lateral roots, leaves, and flowers during postembryonic development. Organ primordia develop from founder cell populations into organs by coordinated cell division and differentiation. Here, we show that organ formation in...
In contrast to our increasingly detailed understanding of how synaptic plasticity provides a cellular substrate for learning and memory, it is less clear how a neuron's voltage-gated ion channels interact with plastic changes in synaptic strength to influence behavior. We find, using generalized and regional knockout mice, that deletion of the HCN1 channel causes profound motor learning and memory...
Rad53 and Mec1 are protein kinases required for DNA replication and recovery from DNA damage in Saccharomyces cerevisiae. Here, we show that rad53, but not mec1 mutants, are extremely sensitive to histone overexpression, as Rad53 is required for degradation of excess histones. Consequently, excess histones accumulate in rad53 mutants, resulting in slow growth, DNA damage sensitivity, and chromosome...
The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1β and BS69, and localizes to sites of repair following...
Checkpoint proteins are activated in response to genotoxic insults or replication stress to maintain genome integrity. Their function is believed to depend largely on the detection of the DNA damage or defects occurring during replication fork progression.
How does FGF (fibroblast growth factor) signaling induce both neural and mesodermal cell fates in the early embryo? Two papers address this fundamental question in this issue of Cell. Bertrand et al. show in the ascidian that a GATA factor determines the neural response of animal cells to FGF signaling, while in the chick, Sheng et al. demonstrate that the slow induction by FGF of a new transcription...
The ability to internalize macromolecules by endocytosis is a property of all eukaryotic cells. Frontline research on endocytosis has been presented in a successful series of biannual meetings in Europe. This year's meeting on ''Membrane Dynamics in Endocytosis'' was held September 13-18 in Acquafredda di Maratea, on the coast of southern Italy. Four key questions were addressed: What are the molecular...
Mutations in either the TSC1 or TSC2 tumor suppressor gene are responsible for Tuberous Sclerosis Complex. The gene products of TSC1 and TSC2 form a functional complex and inhibit the phosphorylation of S6K and 4EBP1, two key regulators of translation. Here, we describe that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway. Under energy...
Gastrulation generates mesoderm and endoderm from embryonic epiblast; soon after, the neural plate is established within the epiblast-both events require FGF signaling. We describe a zinc finger transcriptional activator, Churchill (ChCh), which acts as a switch between different roles of FGF. FGF induces ChCh slowly; this activates Smad-interacting-protein-1 (Sip1), which blocks further induction...
The transcription factor NF-κB is critical for setting the cellular sensitivities to apoptotic stimuli, including DNA damaging anticancer agents. Central to NF-κB signaling pathways is NEMO/IKKγ, the regulatory subunit of the cytoplasmic IκB kinase (IKK) complex. While NF-κB activation by genotoxic stress provides an attractive paradigm for nuclear-to-cytoplasmic signaling pathways, the mechanism...
Mitochondria are tailored to meet the metabolic and signaling needs of each cell. To explore its molecular composition, we performed a proteomic survey of mitochondria from mouse brain, heart, kidney, and liver and combined the results with existing gene annotations to produce a list of 591 mitochondrial proteins, including 163 proteins not previously associated with this organelle. The protein expression...
In this issue, Hughes-Davies et al. describe a novel gene product, EMSY, which suppresses the transactivational activity of BRCA2. EMSY is located within an amplicon in sporadic breast and ovarian cancers, suggesting that its overexpression may mimic the effects of BRCA2 inactivation. The implications for BRCA2 function are discussed.
In chordates, formation of neural tissue from ectodermal cells requires an induction. The molecular nature of the inducer remains controversial in vertebrates. Here, using the early neural marker Otx as an entry point, we dissected the neural induction pathway in the simple embryos of Ciona intestinalis. We first isolated the regulatory element driving Otx expression in the prospective neural tissue,...
Various cell shapes are encountered in the prokaryotic world, but how they are achieved is poorly understood. Intermediate filaments (IFs) of the eukaryotic cytoskeleton play an important role in cell shape in higher organisms. No such filaments have been found in prokaryotes. Here, we describe a bacterial equivalent to IF proteins, named crescentin, whose cytoskeletal function is required for the...
The ubiquitin proteasome system classically selects its substrates for degradation by tagging them with ubiquitin. Here, we describe another means of controlling proteasome function in a global manner. The 26S proteasome can be inhibited by modification with the enzyme, O-GlcNAc transferase (OGT). This reversible modification of the proteasome inhibits the proteolysis of the transcription factor Sp1...
The eukaryotic initiation factor 4G (eIF4G) is the core of a multicomponent switch controlling gene expression at the level of translation initiation. It interacts with the small ribosomal subunit interacting protein, eIF3, and the eIF4E/cap-mRNA complex in order to load the ribosome onto mRNA during cap-dependent translation. We describe the solution structure of the complex between yeast eIF4E/cap...
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