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PubMed1982

Control of in vivo (cellular) phleomycin sensitivity by nuclear genotype, growth phase, and metal ions.

Nuclear genotype, growth phase, and the presence of metal ions all proved to be important in controlling the lethal effects of phleomycin in eukaryotic Saccharomyces cerevisiae. Among 120 normal and radiation-sensitive strains compared for their sensitivities to lethal effects of phleomycin, all mutant strains exhibiting enhanced sensitivities to phleomycin killing were also sensitive to killing by ionizing radiation. Mutants exhibiting sensitivities to phleomycin similar to normal strains of the same ploidy were sensitive to ultraviolet radiation. We conclude that cellular recovery from phleomycin-induced damage in yeast depends upon the function of some or all of 13 independent genes and upon at least some of the same steps in cellular pathways for the biological repair of damage by ionizing radiation. In this respect, the action of phleomycin is similar to the action of its structurally similar analog, bleomycin, even though phleomycin was substantially more cytotoxic. Stationary-phase haploid yeast cells were more sensitive than exponentially growing cells to killing by phleomycin. Survival of stationary-phase yeast was reduced to 0.3 +/- 0.07% (S.E.) after 20-min exposures to phleomycin (1 microgram/ml; approximately 6.7 x 10(-7) M), but lethal effects of phleomycin were completely eradicated (98% survival) by the presence of 0.05 M ethylenediaminetetraacetate during the treatment period. The inactivation indicates an important role for one or more metal ion(s) in the in vivo toxicity of the phleomycin-bleomycin group of anticancer antibiotics.

Bleomycin↗

PubMed1984

Plasma proteinase inhibitors.

Plasma proteinase inhibitors account for about 10% of the total protein in plasma. They provide one mechanism for the control of proteinase activity, thus regulating many important biological reactions such as blood coagulation. Most plasma inhibitors are specific for one or a few related proteinases and control a particular biological event or pathway. Two other inhibitors, the alpha 2-macroglobulin (alpha 2M) and the alpha 1-proteinase (alpha 1PI = alpha 1-antitrypsin) have a broader specificity. The role of alpha 1PI, although theoretically able to inhibit a large number of enzymes, is the inhibition of leukocytic elastase. This function is particularly important in the lung where elastase may be released from neutrophils particularly in smokers. alpha 2-Macroglobulin reacts with a large number of very different proteinases by a mechanism quite different from those of the other inhibitors. The physiological role of this inhibitor is not clearly understood although it may act as a "back-up" inhibitor when levels of other inhibitors are low or if no specific inhibitor is available.

Antithrombin III↗

PubMedDate not supplied

Interspecies and intraspecies DNA homology among established species of Acholeplasma: a review.

Radiolabeled DNA probes prepared in vitro by the nick translation method were used to determine the nucleotide sequence homology among the eight established and one unclassified species of Acholeplasma. Very little DNA homology (2 to 21 percent) was found among these nine distinct species and the heteroduplexes showed at least 15 percent mismatching as determined by thermal elution endpoints. The data obtained by hybridization analyses paralleled the results obtained by the growth inhibition and epi-immunofluorescence serologic procedures. The small amount of nucleotide sequence homology among the nine distinct species indicate that the Acholeplasma species are quite distinct and unrelated to each other genomically, findings which should provide useful insight on the molecular biology and evolutionary pathways of these organisms. Labeled 3H-DNA probes to five strains of either A. laidlawii or A. axanthum hybridized to a varying degree to excess amounts of unlabeled DNAs from 12 strains of A. laidlawii and six strains of A. axanthum, respectively. Nucleic acid hybridization analyses showed a wide variation (48 to 100 percent) in DNA homologies among different strains of the two species. The results demonstrate that strains of A. laidlawii and/or A. axanthum isolated from diverse hosts and habitats (birds, rodents, cats, swine, sheep, cattle, horses, goats, primates, and plants) exhibit extensive genotypic variations. 3H-DNA-DNA hybridization procedures were found to be extremely useful in establishing or confirming the existence of distinct species within the genus Acholeplasma.

Acholeplasma↗

PubMed1995

Biochemical and mutagenic analysis of the melanoma tumor suppressor gene product/p16.

P16 was originally discovered by its ability to interact with CDK4 and to specifically inhibit the catalytic activity of the CDK4/D1 kinase. Increased attention has focused on the p16 gene because of its location on chromosome 9p21, a region involved in chromosomal rearrangements in a large number of tumor types. The p16 gene is also mutated in a large number of tumor cell lines and primary tumor cells. Furthermore, linkage analysis studies suggest that the p16 gene is involved in familial melanoma susceptibility. Due to the oncogenic potential of mutations in this tumor suppressor, it is important to identify and characterize those mutations which alter p16 activity. We have performed a systematic analysis of melanoma associated p16 mutants and of mutants generated in charge to Ala mutagenesis. Using microtiter plate assays to measure both p16-cdk4 binding and cdk4/D1 kinase activity, we show here that the melanoma associated mutants are defective, as are some of the Ala mutants. These results support the idea that p16 mutation, via its deregulation of the cdk4/D1 pathway, is of biological significance in the development of melanoma. Furthermore, we have defined a region within the p16 molecule in which changes are likely to result in a defective protein.

Alanine↗

PubMed1996

A sigma factor that modifies the circadian expression of a subset of genes in cyanobacteria.

We isolated mutants affected in the circadian expression of the psbAI gene in Synechococcus sp. strain PCC 7942 using a strategy that tags the genomic locus responsible for the mutant phenotype. The search identified one short period (22 h) mutant (M2) and two low amplitude mutants, one of which showed apparent arhythmia (M11) and one that was still clearly rhythmic (M16). We characterized the disrupted locus of the low amplitude but still rhythmic mutant (M16) as the rpoD2 gene, a member of a gene family that encodes sigma70-like transcription factors in Synechococcus. We also inactivated rpoD2 in a number of reporter strains and showed that the circadian expression of some genes is not modified by the loss of this sigma factor. Therefore, we conclude that rpoD2 is a component of an output pathway of the biological clock that affects the circadian expression of a subset of genes in Synechococcus. This work demonstrates a direct link between a transcription factor and the manifestation of circadian gene expression.

Amino Acid Sequence↗

PubMed1996

[Urea transporters].

Water and urea use different pathways to cross biological membranes: channels and carriers. Numerous water channels were cloned (aquaporins); only two urea transporters are characterized in mammalians (UT2 and UT11) with sequence homologies suggesting two different carriers. This was confirmed by different localizations: UT2 was only found in renal medulla and probably was the AVP-sensitive urea carrier while UT11 was found in testis, spleen, brain and kidney and represents the constitutive urea carrier described in red blood cell. UT2 hybridized two transcripts, 4.1 kb and 2.9 kb. The large transcript expression was regulated by low protein diet whereas the short transcript was regulated by hydratation conditions. The heterologous expression into Xenopus oocytes showed a large increase of the urea uptake (UT2 > UT11), inhibitable by phloretin for UT11 and UT2 and by pCMBS only for UT11. A saturable transport of thiourea was only observed into oocytes expressing UT11. Moreover, hUT11 is encoded by the kidd locus, but, Jk (a-b-) individuals, in the absence of this urea transporter did not present related pathology. Other carriers still have to be identified and characterized in different renal segments and other tissues.

Animals↗

PubMed1997

[Ras proteins in Saccharomyces cerevisiae, their partners and their activation].

Ras proteins play the role of molecular switches by conformational change between a GTP and a GDP-bound state. In the yeast Saccharomyces cerevisiae, they are encoded by two partially redundant genes RAS1 and RAS2 with a different pattern of gene expression. They are essential for growth because they are required for the activation of the adenylate cyclase and thus the protein kinase A pathway. Other possible biological functions remains to be established. To achieve their biological function, they need to be processed after their synthesis, they are modified farnesylated and palmitoylated at their C-terminal end at their CaaX box. Palmitoylation, involved in membrane localization, is not essential for growth but required for glucose signaling whereas farnesylation appears to participate in adenylate cyclase activation. In the GTP-bound state ras proteins interact through their conserved effector domain with the adenylate cyclase, the product of the CYR1/CDC35 gene. They also interact with GTPase activating proteins encoded by IRA1 and IRA2. These proteins are specific for yeast ras. It has been shown that Ira2p recognizes specific residues of yeast ras not shared by mammalian ras. The interaction with the guanine nucleotide exchange factor (GEF) of the CDC25 family is enhanced by dominant negative mutations such as RAS2ala22. Using the two hybrid approach, we have showed the key role of position 80 in Ras2p and confirmed the involvement of the a2 helix, the other switching part of ras, in this interaction and the induced effect. As a counterpart we have identified positions in HGRF55 conserved in other GEF involved in ras interaction. The triggering elements of ras activation: the GEF Cdc25p and Sdc25p are limiting components of the ras system. Cdc25p is part of a multimolecular complex associated with the membrane. We have shown that it can form homodimers and heterodimers with Sdc25p. It is an unstable protein containing a cyclin destruction box. Therefore its activity on ras could be regulated by controlling its cellular content.

Adenylyl Cyclases↗

PubMed1995

Execution and suicide: cytotoxic lymphocytes enforce Draconian laws through separate molecular pathways.

With the ability to analyze cytotoxicity in animals deficient in effector molecules, the debate over the biological significance of individual effector pathways is finally being settled. For CD8+ cytotoxic T lymphocytes, the two primary cytotoxic pathways are mediated by the Fas ligand and perforin. The dichotomy between the two killing pathways is mirrored in the dichotomy between their biological roles: the primary function of the Fas ligand is the control of normal cell renewal by inducing programmed cell death of actively proliferating cells via the Fas pathway. This type of cell death is part of the normal endogenous homeostatic mechanism responsible for maintaining rapidly changing cell populations such as clonally expanding and contracting T cells. In contrast, the biological function of perforin and associated granule proteins is the killing and elimination of parasitized, non-compliant cells that arise as part of pathophysiological processes and may resist lysis pathways signalled to induce apoptosis. Thus, the main function of perforin and granzymes is the maintenance of immune surveillance against both exogenous and endogenous hazards.

Animals↗

PubMed1991

Ultracytochemistry of the secretory pathway in Saccharomyces cerevisiae defies the established pathway model.

The molecular and cell biologic data supporting the established model of the intracellular secretory (transport) pathway for glycoproteins in the yeast Saccharomyces cerevisiae have been reviewed and confronted with our electron-cytochemical findings. These in situ findings show a new class of constitutive intracellular conveyors--the coated globules--and also suggest substantial alternatives in the cellular mechanism of the vacuole biogenesis. The controversial question of the Golgi compartment identity in S. cerevisiae is revived.

Dipeptidyl-Peptidases and Tripeptidyl-Peptidases↗

PubMed2026

Histopathological evaluation of RPL5 expression in triple-negative breast cancer: an integrated immunohistochemical and transcriptomic study.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high invasiveness, limited therapeutic options, and unfavorable clinical outcomes. Ribosomal protein L5 (RPL5), a component of the large ribosomal subunit, has been implicated in ribosome biogenesis, translational regulation, and p53-associated cellular processes. This study investigated the immunohistochemical expression pattern of RPL5 in TNBC tissues and explored its potential biological significance through integrated transcriptomic analyses. Tumor tissues from 37 patients with TNBC and 7 adjacent non-tumorous breast tissues were collected from the Affiliated Tumor Hospital of Xinjiang Medical University between December 2017 and December 2023. RPL5 protein expression was evaluated by immunohistochemistry, and its association with clinicopathological characteristics was analyzed. Public transcriptomic datasets from TCGA-BRCA and GEO were further used to validate RPL5 expression patterns in TNBC. Co-expression analysis and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate potential biological functions and signaling pathways associated with RPL5. Immunohistochemical analysis demonstrated significantly lower RPL5 protein expression in TNBC tissues compared with adjacent normal breast tissues (p=0.001). In contrast, transcriptomic analyses revealed significantly higher RPL5 expression in TNBC compared with non-TNBC breast cancer subtypes (p<0.001). No significant associations were observed between RPL5 expression and clinicopathological parameters, including age, tumor size, menopausal status, TNM stage, histological grade, or lymph node metastasis (all p>0.05). Survival analysis showed no significant difference in overall survival between patients with high and low RPL5 expression. Functional enrichment analyses indicated that RPL5-related genes were predominantly involved in ribosome biogenesis, translational regulation, and p53-related signaling pathways. These findings suggest that abnormal RPL5 expression may be associated with TNBC biology through ribosome-related programs, although causal roles require functional validation. RPL5 may represent a potential histopathological and molecular indicator associated with TNBC biology, although its precise functional role requires further experimental validation.

Humans↗

PubMed1992

Cell biology of viruses that assemble along the biosynthetic pathway.

In this review we discuss five groups of viruses that bud into, or assemble from, different compartments along the biosynthetic pathway. These are herpes-, rota-, corona-, bunya- and pox-viruses. Our main emphasis will be on the virally-encoded membrane glycoproteins that are responsible for determining the site of virus assembly. In a number of cases these proteins have been well characterized and appear to serve as resident markers of the budding compartments. The assembly and dissemination of these viruses raises many questions of cell biological interest.

Animals↗

PubMed2001

Transcriptional regulation by Smads: crosstalk between the TGF-beta and Wnt pathways.

BACKGROUND: Several studies have shown that cooperation between transforming growth factor beta (TGF-beta) and Wnt/wingless signaling pathways plays a role in controlling certain developmental events. These factors elicit their biological effects through distinct pathways in which TGF-beta and Wnt signaling induce activation of the transcriptional regulators Smads and lymphoid enhancer binding factor/T-cell-specific factor (LEF/TCF), respectively. To understand the mechanism for cooperativity between these pathways, we have investigated the molecular mechanism for this synergistic effect. METHODS: Transcriptional assays were conducted by transient transfection of HepG2 cells with use of luciferase reporter constructs. Protein/protein interaction studies were conducted in vitro with the use of glutathione-S-transferase pull-down assays and in intact cells by immunoprecipitation and immunoblotting. RESULTS: We show that Smads physically interact with LEF1/TCF transcription factors and that specific DNA binding sites in the Xenopus twin promoter are required for synergistic activation by TGF-beta and Wnt pathways. In addition, we demonstrate that TGF-beta-dependent activation of LEF1/TCF target genes can occur independently of beta-catenin, an essential component of the Wnt signaling pathway. CONCLUSIONS: TGF-beta and Wnt signaling pathways can independently or cooperatively regulate LEF1/TCF target genes. This suggests that the cooperation between these pathways may be important for the specification of cell fates during development.

Animals↗

PubMed1993

[Obsessive compulsive disorders].

Obsessive compulsive disorders (OCD) are a nosographic entity. Their biological rating in serotonergic pathways and the efficacy of serotonergic antidepressants allows for developing a clinical and biological models of OCD. J. Guyotat, one of the first in 1959 to observe the favorable effects of antidepressants on OCD, presents their history. Epidemiological surveys conducted since 1980 have shown that the prevalence of OCD was underestimated until then. The prevalence is 2 to 3% in the adult population, with more women affected. The disorder develops early in childhood and adolescence. Loss of time is an important criteria for OCD but, according to M. Bourgeois, who reviewed the symptoms precisely, this does not warrant identifying a separate "primary obsessive slowness" syndrome. According to M. Bouvard, the prognosis of the disorder, in contrast to that for rituals observed in children between 3 and 5 years of age, is poor, with a risk of chronicity and social disturbances. The prevalence of OCD in children and adolescents is 0.8% and remains stable. The comorbidity, in particular with tics, is discussed. The favorable effects of fluoxetine are reported. J.M. Chignon reviews the concept of comorbidity, developed in internal medicine, and explains that it could be rigorously applied to psychiatry only starting with the DSM III-R. The comorbidity of OCD with other psychiatric diseases is highly variable: it is reviewed for personality disorders (0 to 55%), schizophrenia (4%), substance abuse (10%) and especially depression: one third of patients with OCD will develop a major depressive episode. Based on a clinical case report, M. Faruch leads us from symptoms to behavior therapy. The symptom must be considered for itself, whether it is part or not of the obsessive neurosis. It is legitimate to use antidepressants in combination with behavior therapy.

Adolescent↗

PubMed2026

Bioinformatics Analysis and Experimental Validation of Key Genes Associated With Hypoxia and Ischemia in Myocardial Infarction.

BACKGROUND: This study aimed to screen and identify core hypoxia-ischemia-related genes associated with myocardial infarction (MI). METHOD: Two transcriptomic datasets, GSE97320 and GSE48060, were retrieved from the Gene Expression Omnibus (GEO) database. After data integration and batch effect elimination, differential expression analysis was performed to screen differentially expressed genes (DEGs), and the corresponding visualization analysis was conducted. Hypoxia-ischemia-related genes were acquired from the GeneCards database; hypoxia-ischemia related genes (HIRGs) were subsequently identified by intersecting the retrieved genes with screened DEGs. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were implemented to explore the biological functions and underlying signaling pathways of HIRGs. A combination of protein-protein interaction (PPI) network analysis and random forest (RF) algorithm was applied to screen hub genes from HIRGs. The external GEO dataset GSE66360 was utilized to validate the expression patterns of candidate hub genes. Furthermore, an acute myocardial infarction (AMI) mouse model was established, and quantitative real-time polymerase chain reaction (qPCR) was performed to detect the mRNA expression levels of hub genes in myocardial tissues for in vivo validation. RESULTS: A total of 633 DEGs and 308 hypoxia-ischemia-related genes were screened in the present study, among which 21 overlapping HIRGs were obtained. PLAUR and IL1B were finally identified as two hub genes from HIRGs based on PPI network and random forest algorithm. The qPCR results revealed that the expression levels of PLAUR and IL1B were significantly upregulated in the AMI group compared with the sham operation group (p < 0.05). CONCLUSION: The present findings demonstrated that PLAUR and IL1B serve as pivotal genes involved in the pathological hypoxia-ischemia process of AMI. These two genes may act as novel biomarkers and promising therapeutic targets for the recognition and clinical intervention of hypoxia-ischemia injury following AMI.

Myocardial Infarction↗

PubMed2000

The influence of childhood weight and socioeconomic status on change in adult body mass index in a British national birth cohort.

OBJECTIVE: To investigate the effect of childhood weight and childhood socioeconomic status on the pattern of change in body mass index (BMI) between 20 and 43 years. METHODS: A British birth cohort study where the survey members have been followed up regularly since their birth in 1946, with the most recent of 19 follow-ups when the cohort were aged 43 years. BMI was available at 20, 26, 36 and 43 years of age and thus multilevel models for repeated outcome measures were used to model the patterns of change in BMI. RESULTS: The rate of increase in BMI with age was non-linear, with the rate of increase in mean BMI accelerating with increasing age at different rates for men and women. The mean BMI for men was higher than that for women at all ages. Childhood manual social class, defined in terms of father's occupation, and high relative weight at 14 years of age were associated with higher mean BMI across adult life, and these effects increased with age. The effects of childhood relative weight and social class were independent of educational attainment and adult social class. CONCLUSION: The study provides evidence of a long-term effect of childhood social and biological circumstances on BMI. The pathways underlying these relationships may be social or biological, but are not yet fully understood.

Adolescent↗

PubMed2002

Two novel metabolic pathways of 22-oxacalcitriol (OCT). C-25 dehydration and C-3 epimerization and biological activities of novel OCT metabolites.

22-Oxacalcitriol (OCT) is an analog of calcitriol, characterized by potent differentiation-inducing activity and low calcemic liability. The metabolism of OCT has been studied and its polar metabolites, such as 24/26-hydroxylated-OCT and hexanor-1 alpha,20-dihydroxyvitamin D(3) (1 alpha,20(OH)(2)D(3)), have been identified. In contrast, little is known about the less polar metabolites of OCT, which have been found in relatively large amounts. In this study, the in vitro metabolism of OCT was studied in UMR 106, Caco-2, and LLC-PK(1) cells to identify the less polar metabolites and to assess their biological activity. OCT was initially metabolized to three less polar metabolites, 3-epi-OCT and two dehydrates, 25-dehydroxy- 25-ene-22-oxa-1 alpha(OH)D(3) (25-ene-22-oxa-1 alpha(OH)D(3)) and 25-dehydroxy-24-ene-22-oxa-1 alpha(OH)D(3) (24-ene-22-oxa-1 alpha(OH)D(3)). We also observed further metabolites, the two C-3 epimers of the C-25 dehydrates, 25-ene-3-epi-22-oxa-1 alpha(OH)D(3) and 24-ene-3-epi-22-oxa-1 alpha(OH)D(3). The structures of these metabolites were successfully assigned by (1)H NMR and LC-MS analyses. The three cell lines differ in their ability to metabolize OCT through the C-3 epimerization or the C-25 dehydration pathway. The biological activity of the OCT metabolites assessed by a luciferase reporter gene transcriptional activation system, binding assays for the vitamin D receptor (VDR) and vitamin D-binding protein (DBP), and assays for regulatory activities of cell differentiation and proliferation was found to be lower than that of OCT. Thus, both the C-3 epimerization and C-25 dehydration may work to reduce the biological activity of OCT.

Animals↗

PubMed1998

Gene discovery in Drosophila: new insights for learning and memory.

Genetic approaches have been used to investigate increasingly complex biological systems. Here we review the current state of genetic analysis of learning and memory in the fruitfly, Drosophila melanogaster. Emerging findings support two main themes. First, discovery and manipulation of genes involved with behavioral plasticity in genetically accessible systems such as D. melanogaster enables dissection of the biochemical, cellular, anatomical, and behavioral pathways of learning and memory. Second, because core cellular mechanisms of simple forms of learning are evolutionarily conserved, biological pathways discovered in invertebrates are likely to be conserved in vertebrate systems as well.

Animals↗

PubMed2001

Glycobiology of surface layer proteins.

Over the last two decades, a significant change of perception has taken place regarding prokaryotic glycoproteins. For many years, protein glycosylation was assumed to be limited to eukaryotes; but now, a wealth of information on structure, function, biosynthesis and molecular biology of prokaryotic glycoproteins has accumulated, with surface layer (S-layer) glycoproteins being one of the best studied examples. With the designation of Archaea as a second prokaryotic domain of life, the occurrence of glycosylated S-layer proteins had been considered a taxonomic criterion for differentiation between Bacteria and Archaea. Extensive structural investigations, however, have demonstrated that S-layer glycoproteins are present in both domains. Among Gram-positive bacteria, S-layer glycoproteins have been identified only in bacilli. In Gram-negative organisms, their presence is still not fully investigated; presently, there is no indication for their existence in this class of bacteria. Extensive biochemical studies of the S-layer glycoprotein from Halobacterium halobium have, at least in part, unravelled the glycosylation pathway in Archaea; molecular biological analyses of these pathways have not been performed, so far. Significant observations concern the occurrence of unusual linkage regions both in archaeal and bacterial S-layer glycoproteins. Regarding S-layer glycoproteins of bacteria, first genetic data have shed some light into the molecular organization of the glycosylation machinery in this domain. In addition to basic S-layer glycoprotein research, the biotechnological application potential of these molecules has been explored. With the development of straightforward molecular biological methods, fascinating possibilities for the expression of prokaryotic glycoproteins will become available. S-layer glycoprotein research has opened up opportunities for the production of recombinant glycosylation enzymes and tailor-made S-layer glycoproteins in large quantities, which are commercially not yet available. These bacterial systems may provide economic technologies for the production of biotechnologically and medically important glycan structures in the future.

Archaeal Proteins↗