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Recent evidence indicates that gradients of the same extracellular molecules can act as both morphogens, specifying cell differentiation, and guidance cues, directing axon movement. We discuss how cells may use common mechanisms to convert graded information into discrete responses; and how extracellular signals provide coordinate systems that can be linked to highly diverse cellular outputs.
Transport of the essential amino acids arginine and lysine is critical for the survival of mammalian cells. The adaptive response to nutritional stress involves increased translation of the arginine/lysine transporter (cat-1) mRNA via an internal ribosome entry site (IRES) within the mRNA leader. Induction of cat-1 IRES activity requires both translation of a small upstream open reading frame (uORF)...
Skeletal muscle formation and growth require the fusion of myoblasts to form multinucleated myofibers or myotubes, but few molecules are known to regulate myoblast fusion in mammals. The transcription factor NFATc2 controls myoblast fusion at a specific stage of myogenesis after the initial formation of a myotube and is necessary for further cell growth. By examining genes regulated by NFATc2 in muscle,...
Histone lysine methylation plays a key role in the organization of chromatin structure and the regulation of gene expression. Recent studies demonstrated that the yeast Set1 and Set2 histone methyltransferases are recruited to mRNA coding regions by the PAF transcription elongation complex in a manner dependent upon the phosphorylation state of the carboxy-terminal domain of RNA polymerase II. These...
Spinocerebellar ataxia type 1 (SCA1) is one of several neurological disorders caused by a CAG repeat expansion. In SCA1, this expansion produces an abnormally long polyglutamine tract in the protein ataxin-1. Mutant polyglutamine proteins accumulate in neurons, inducing neurodegeneration, but the mechanism underlying this accumulation has been unclear. We have discovered that the 14-3-3 protein, a...
Embryonic stem (ES) cells derived from the inner cell mass (ICM) of blastocysts grow infinitely while maintaining pluripotency. Leukemia inhibitory factor (LIF) can maintain self-renewal of mouse ES cells through activation of Stat3. However, LIF/Stat3 is dispensable for maintenance of ICM and human ES cells, suggesting that the pathway is not fundamental for pluripotency. In search of a critical...
Analysis of the system design principles of signaling systems requires model systems where all components and regulatory interactions are known. Components of the Lac and Ntr systems were used to construct genetic circuits that display toggle switch or oscillatory behavior. Both devices contain an ''activator module'' consisting of a modified glnA promoter with lac operators, driving the expression...
The therapeutic potential of stem cells and nuclear cloning has led to renewed interest in classical models of regeneration. This longstanding problem is undergoing a renaissance spurred by the availability of new techniques that finally allow analysis on the cellular and molecular level.
Telomerase-mediated healing of broken chromosomes gives rise to terminal deletions and is repressed in most organisms. In ciliated protozoa, however, chromosome fragmentation and de novo telomere addition are part of the developmental program. Work by Karamysheva et al. (2003) in this issue of Cell indicates that in Euplotes crassus, this is mediated through switching between different telomerase...
Meetings held in late April to mark the 50 th anniversary of the elucidation of the DNA double helix covered the past, present, and future of DNA biology.
Monoubiquitination serves as a regulatory signal in a variety of cellular processes. Monoubiquitin signals are transmitted by binding to a small but rapidly expanding class of ubiquitin binding motifs. Several of these motifs, including the CUE domain, also promote intramolecular monoubiquitination. The solution structure of a CUE domain of the yeast Cue2 protein in complex with ubiquitin reveals...
Most gram-negative pathogens express fibrous adhesive virulence organelles that mediate targeting to the sites of infection. The F1 capsular antigen from the plague pathogen Yersinia pestis consists of linear fibers of a single subunit (Caf1) and serves as a prototype for nonpilus organelles assembled via the chaperone/usher pathway. Genetic data together with high-resolution X-ray structures corresponding...
The first structures have been obtained for complexes between CUE domains and monoubiquitin, one by NMR (Kang et al., this issue of Cell) and one by X-ray crystallography (Prag et al., this issue of Cell), thus providing insights into ubiquitin recognition by CUE domains. Structural comparisons suggest that different CUE surfaces can interact with ubiquitin, indicating that not all CUE domains are...
Riboswitches are metabolite binding domains within certain messenger RNAs that serve as precision sensors for their corresponding targets. Allosteric rearrangement of mRNA structure is mediated by ligand binding, and this results in modulation of gene expression. We have identified a class of riboswitches that selectively recognizes guanine and becomes saturated at concentrations as low as 5 nM. In...
Embryonic stem (ES) cells undergo extended proliferation while remaining poised for multilineage differentiation. A unique network of transcription factors may characterize self-renewal and simultaneously suppress differentiation. We applied expression cloning in mouse ES cells to isolate a self-renewal determinant. Nanog is a divergent homeodomain protein that directs propagation of undifferentiated...
The primary function of telomerase is to maintain preexisting telomere tracts. In the ciliate Euplotes crassus, however, telomerase RNP structure and substrate recognition are altered during macronuclear development to facilitate de novo telomere addition. We found that E. crassus harbors three TERT genes encoding the telomerase catalytic subunit that not only vary in their nucleotide and predicted...
Axon outgrowth is the first step in the formation of neuronal connections, but the pathways that regulate axon extension are still poorly understood. We find that mice deficient in calcineurin-NFAT signaling have dramatic defects in axonal outgrowth, yet have little or no defect in neuronal differentiation or survival. In vitro, sensory and commissural neurons lacking calcineurin function or NFATc2,...
Coupling of ubiquitin conjugation to ER degradation (CUE) domains are ~50 amino acid monoubiquitin binding motifs found in proteins of trafficking and ubiquitination pathways. The 2.3 Å structure of the Vps9p-CUE domain is a dimeric domain-swapped variant of the ubiquitin binding UBA domain. The 1.7 Å structure of the CUE:ubiquitin complex shows that one CUE dimer binds one ubiquitin molecule. The...
In this issue of Cell, Chambers et al. (2003) and Mitsui et al. (2003) add a new transcriptional operating system to the known Oct4 and Stat3 systems required for early embryonal stem cell potency and self-renewal. Nanog, a homeobox transcription factor, plays a crucial role in the second embryonic cell fate specification following formation of the blastocyst.
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