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<jats:p> The adenomatous polyposis coli (APC) tumor suppressor protein binds to β-catenin, a protein recently shown to interact with Tcf and Lef transcription factors. The gene encoding hTcf-4, a Tcf family member that is expressed in colonic epithelium, was cloned and characterized. hTcf-4 transactivates transcription only when associated with β-catenin. Nuclei of APC <jats:sup>−/−</jats:sup> colon carcinoma cells were found to contain a stable β-catenin-hTcf-4 complex that was constitutively active, as measured by transcription of a <jats:italic>Tcf</jats:italic> reporter gene. Reintroduction of APC removed β-catenin from hTcf-4 and abrogated the transcriptional transactivation. Constitutive transcription of <jats:italic>Tcf</jats:italic> target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium. </jats:p>

<jats:p> Inactivation of the adenomatous polyposis coli ( <jats:italic>APC</jats:italic> ) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by β-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant <jats:italic>APC</jats:italic> genes present in colorectal tumors were found to be defective in this activity. Furthermore, colorectal tumors with intact <jats:italic>APC</jats:italic> genes were found to contain activating mutations of β-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of β-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or β-catenin. </jats:p>

<jats:p> Signal transduction by β-catenin involves its posttranslational stabilization and downstream coupling to the Lef and Tcf transcription factors. Abnormally high amounts of β-catenin were detected in 7 of 26 human melanoma cell lines. Unusual messenger RNA splicing and missense mutations in the β-catenin gene ( <jats:italic>CTNNB1</jats:italic> ) that result in stabilization of the protein were identified in six of the lines, and the adenomatous polyposis coli tumor suppressor protein (APC) was altered or missing in two others. In the APC-deficient cells, ectopic expression of wild-type APC eliminated the excess β-catenin. Cells with stabilized β-catenin contained a constitutive β-catenin-Lef-1 complex. Thus, genetic defects that result in up-regulation of β-catenin may play a role in melanoma progression. </jats:p>

<jats:p>The “Spanish” influenza pandemic killed at least 20 million people in 1918–1919, making it the worst infectious pandemic in history. Understanding the origins of the 1918 virus and the basis for its exceptional virulence may aid in the prediction of future influenza pandemics. RNA from a victim of the 1918 pandemic was isolated from a formalin-fixed, paraffin-embedded, lung tissue sample. Nine fragments of viral RNA were sequenced from the coding regions of hemagglutinin, neuraminidase, nucleoprotein, matrix protein 1, and matrix protein 2. The sequences are consistent with a novel H1N1 influenza A virus that belongs to the subgroup of strains that infect humans and swine, not the avian subgroup.</jats:p>

<jats:p> Prenylated proteins contain a covalently linked cholesterol intermediate near their carboxyl-termini. Maturation of most prenylated proteins involves proteolytic removal of the last three amino acids. Two genes in <jats:italic>Saccharomyces cerevisiae</jats:italic> , <jats:italic>RCE1</jats:italic> and <jats:italic>AFC1</jats:italic> , were identified that appear to be responsible for this processing. The Afc1 protein is a zinc protease that participates in the processing of yeast <jats:bold>a</jats:bold> -factor mating pheromone. The Rce1 protein contributes to the processing of both Ras protein and <jats:bold>a</jats:bold> -factor. Deletion of both <jats:italic>AFC1</jats:italic> and <jats:italic>RCE1</jats:italic> resulted in the loss of proteolytic processing of prenylated proteins. Disruption of <jats:italic>RCE1</jats:italic> led to defects in Ras localization and signaling and suppressed the activated phenotype associated with the allele <jats:italic> RAS2 <jats:sup>val19</jats:sup> </jats:italic> . </jats:p>

<jats:p>Protein farnesyltransferase (FTase) catalyzes the carboxyl-terminal lipidation of Ras and several other cellular signal transduction proteins. The essential nature of this modification for proper function of these proteins has led to the emergence of FTase as a target for the development of new anticancer therapy. Inhibition of this enzyme suppresses the transformed phenotype in cultured cells and causes tumor regression in animal models. The crystal structure of heterodimeric mammalian FTase was determined at 2.25 angstrom resolution. The structure shows a combination of two unusual domains: a crescent-shaped seven-helical hairpin domain and an α-α barrel domain. The active site is formed by two clefts that intersect at a bound zinc ion. One cleft contains a nine-residue peptide that may mimic the binding of the Ras substrate; the other cleft is lined with highly conserved aromatic residues appropriate for binding the farnesyl isoprenoid with required specificity.</jats:p>

<jats:p>To provide information about dynamic sensory stimuli, the pattern of action potentials in spiking neurons must be variable. To ensure reliability these variations must be related, reproducibly, to the stimulus. For H1, a motion-sensitive neuron in the fly's visual system, constant-velocity motion produces irregular spike firing patterns, and spike counts typically have a variance comparable to the mean, for cells in the mammalian cortex. But more natural, time-dependent input signals yield patterns of spikes that are much more reproducible, both in terms of timing and of counting precision. Variability and reproducibility are quantified with ideas from information theory, and measured spike sequences in H1 carry more than twice the amount of information they would if they followed the variance-mean relation seen with constant inputs. Thus, models that may accurately account for the neural response to static stimuli can significantly underestimate the reliability of signal transfer under more natural conditions.</jats:p>