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OBJECTIVE: To investigate the expression and possible function of the c-mos proto-oncogene in human eggs. DESIGN: Eggs obtained as discarded material from assisted reproductive technology procedures were analyzed for c-mos messenger RNA by reverse transcriptase-polymerase chain reaction. As an approach to investigating c-mos function, we measured maturation-promoting factor (MPF) activity (histone H1 kinase) in eggs without and with inhibition of protein synthesis. Detection of RNA transcripts of c-raf was included as control. RESULTS: Transcripts of c-mos were detected in small fractions of individual eggs, indicating that c-mos is abundantly transcribed. Inhibition of protein synthesis resulted in loss of MPF, leading to chromatin decondensation and reformation of a nucleus. C-raf maternal messages were also detectable in individual human eggs. CONCLUSION: The c-mos proto-oncogene is an abundant maternal message in human eggs as in other species. The effects of inhibiting protein synthesis in human eggs are similar to those obtained in mouse and Xenopus eggs, either as a consequence of protein synthesis inhibition or specific ablation of c-mos RNA by injection of anti-sense oligonucleotides. The c-mos gene product is thus likely to play a critical role in human oocyte meiosis by regulating the activity of MPF.
In 50 patients with a "white hole" in their scintigram--among them 44 patients with a history of myocardial infarction--the relation between its relative volume and the ventriculographically determined ejection fraction was studied retrospectively. A relative volume of the "white hole" larger than 13.7% showed a specificity of 93% and a sensitivity of 45% for a decreased ejection fraction and had a significant correlation of r = -0.54 (alpha = 0.01) with the ejection fraction. Thus the relative volume of the "white hole" derived automatically from 201Tl-SPECT is an easy-to-determine additional parameter which allows an at least semiquantitative statement about the function of the left ventricle.
The significance of conserved cysteines at positions 288, 337, and 369 in the hormone binding domain of the human vitamin D receptor was evaluated by individual site-directed mutagenesis to glycine. Neither nuclear localization nor heterodimerization with retinoid X receptors in binding to the vitamin D-responsive element was appreciably affected by altering these cysteines, but vitamin D hormone (1,25-(OH)2D3) activated transcription was compromised significantly in the C288G and C337G mutants. Only the C288G mutant displayed depressed (3-fold) 1,25-(OH)2D3 ligand binding affinity at 4 degrees C, in vitro, although at elevated temperatures (23-37 degrees C), ligand binding was attenuated severely in C288G, moderately in C337G and very mildly in C369G. The degree of impairment of ligand binding at physiologic temperatures correlated with the requirement for increased concentrations of 1,25-(OH)2D3 ligand to maximally stimulate transcriptional activity in co-transfected COS-7 cells. Thus cysteine 288 and, to a lesser extent, cysteine 337 are important for high affinity hormone binding to the vitamin D receptor, which ultimately leads to ligand-dependent transcriptional activation.
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Cytochrome P450 (P450) monooxygenases catalyze the epoxidation of arachidonic acid to form epoxyeicosatrienoic acids, which modulate bronchial smooth muscle tone and airway transepithelial ion transport. We recently described a new human P450 arachidonic acid epoxygenase (CYP2J2) and the corresponding rat homologue (CYP2J3). Northern analysis of lung RNA using CYP2J cDNA probes demonstrated that CYP2J2 and CYP2J3 mRNAs were expressed in the lung. Immunoblotting of microsomal fractions prepared from human and rat lungs using a polyclonal antibody raised against recombinant human CYP2J2 revealed a single 56-kDa band confirming abundant pulmonary CYP2J2 and CYP2J3 protein expression. Immunohistochemical analysis of formalin-fixed paraffin-embedded human and rat lung sections using the anti-human CYP2J2 IgG and avidin/biotin/peroxidase detection showed that CYP2J proteins were primarily expressed in ciliated epithelial cells lining the airway. Prominent staining was also noted in nonciliated airway epithelial cells, bronchial and pulmonary vascular smooth muscle cells, pulmonary vascular endothelium, and alveolar macrophages, whereas less intense staining was noted in alveolar epithelial cells. Endogenous epoxyeicosatrienoic acids were detected in both human and rat lung using gas chromatography/mass spectrometry, thus providing direct evidence for the in vivo human and rat pulmonary P450 metabolism of arachidonic acid. Based on these data, we conclude that CYP2J2 and CYP2J3 are abundant pulmonary arachidonic acid epoxygenases and that CYP2J products, the epoxyeicosatrienoic acids, are endogenous constituents of human and rat lung. In addition to known effects on airway smooth muscle tone and transepithelial electrolyte transport, the localization of CYP2J proteins to vascular smooth muscle and endothelium suggests that epoxyeicosatrienoic acids may also be involved in the modulation of pulmonary vascular tone.
The anatomy of the wrist and its ligaments is complex and somewhat confusing, particularly to the student of the wrist. This article provides an overview of our current understanding of the anatomy of the wrist ligaments. It unites previously published descriptions with the most recent insights.
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Mapping of the coding sequences of the best characterized subfamilies of G-protein-coupled receptors is performed with unsupervised neural networks based on a winner-take-all strategy. High order features therefrom extracted originate signals along the aligned protein sequences of the different subfamilies. These plots reveal characteristic domains common and/or characteristic of the receptor subfamily. By comparison with the existing experimental results, it is obtained that most of the regions signalled by clustering overlap with possible functional regions in the folded proteins. This is particularly noticeable for the third cytoplasmic loop, which is likely to be involved in the molecular coupling with the G-proteins. The results suggest that functional regions in proteins may be characterized by intrinsic representative features in the coding sequences which can be enlighted by high order mapping.
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PURPOSE: The aim of this study was to screen affected members of glaucoma families for mutations in the Trabecular Meshwork Inducible Glucocorticoid Response (TIGR) gene also known by the name myocilin (MYOC) or by combined names such as TIGR/MYOC. Our primary objectives were (1) to identify mutations responsible for glaucoma in members of three families for which we have shown linkage between chromosome 1 GLC1A-region markers and the primary open angle glaucoma (POAG) phenotype, and (2) to determine the relationship of these and other mutations to key points of predicted function and structure of the TIGR/MYOC protein. METHODS: DNA sequence determination was used to identify sequence changes in sections of the TIGR/MYOC gene that were PCR-amplified from genomic DNA from the probands of three previously-reported GLC1A juvenile-onset POAG families, UM:JG1, UM:JG3, UM:GL57, and unmapped family UM:JG5. Allele-specific oligonucleotide hybridization was used to screen for the identified mutations in PCR-amplified DNA from individual members of each pedigree and from a panel of 11 additional juvenile glaucoma family probands, 42 adult POAG family probands, and 43 normal individuals. Computerized algorithms were used to identify functional motifs and predict structures of normal and mutant forms of the protein. RESULTS: Sequence changes were found that alter amino acids in the olfactomedin-like domain near the carboxy terminal end of the TIGR protein in affected members of families UM:JG1 (Pro370Leu), UM:JG3 (Val426Phe), UM:GL57 (Glu323Lys) and UM:JG5 (Gly252Arg). Co-segregation of glaucoma and Pro370Leu, Val426Phe, and Gly252Arg in known GLC1A families suggests that these are mutations. Although the Gly252Arg substitution observed in UM:JG5 is non-conservative, it was not possible to distinguish whether it is a mutation or a polymorphism. None of the sequence changes described in these families were observed in other juvenile glaucoma cases in this study, nor in any of the POAG or phenotypically normal individuals tested here. Analysis of amino acid sequence changes resulting from mutations described in this and other works demonstrate localization of many mutations in the vicinity of predicted functional motifs in the olfactomedin-like domain. Identification of rat latrophilin (LPH1/CIRL) as a new member of the olfactomedin-like protein family to which TIGR/MYOC belongs suggests that the region of olfactomedin homology is a protein domain that can occur in different protein contexts. CONCLUSIONS: Location of mutations described in this and previous work suggests that some specific predicted protein motifs in the olfactomedin-like domain may be important to TIGR/MYOC function. In some cases, the role of TIGR/MYOC in the etiology of glaucoma may result from alteration of the sequences recognized by modifying enzymes such as casein kinase II. In other cases altered protein folding may affect access of enzymes to their target sequences on TIGR/MYOC. Although modifications and structures discussed here are predicted rather than proven, they provide a useful theoretical framework for design of subsequent experiments. Alterations to protein folding and predicted modification motifs cannot explain the pathogenic mechanisms of all of the known TIGR/MYOC glaucoma mutations.
We describe an algorithm to predict tertiary structures of small proteins. In contrast to most current folding algorithms, it uses very few energy parameters. Given the secondary structural elements in the sequence--alpha-helices and beta-strands--the algorithm searches the remaining conformational space of a simplified real-space representation of chains to find a minimum energy of an exceedingly simple potential function. The potential is based only on a single type of favorable interaction between hydrophobic residues, an unfavorable excluded volume term of spatial overlaps and, for sheet proteins, an interstrand hydrogen bond interaction. Where appropriate, the known disulfide bonds are constrained by a square-law potential. Conformations are searched by a genetic algorithm. The model predicts reasonably well the known tertiary folds of seven out of the 10 small proteins we consider. We draw two conclusions. First, for the proteins we tested, this exceedingly simple potential function is no worse than others having hundreds of energy parameters in finding the right general tertiary structures. Second, despite its simplicity, the potential function is not the weak link in this algorithm. Differences between our predicted structures and the correct targets can be ascribed to shortcomings in our search strategy. This potential function may be useful for testing other conformational search strategies.