p53, p63 and p73 – solos,alliances and feuds among family members

p53 controls crucial stress responses that play a major role in preventing malignant transformation. Hence, inactivation of p53 is the single most common genetic defect in human cancer. With the recent discovery of two close structural homologs, p63 en p73, we are getting a broader view of a fascinating gene family that links developmental biology with tumor biology. While unique roles are apparent for each of these genes, intimate biochemical cross-talk among family members suggests a functional network that might influence many different aspects of individual gene action. The most interesting part of this family network derives from the fact that the p63 and p73 genes are based on the ‘two-genes-in-one’ idea, encoding both agonist and antagonist in the same open reading frame. In this review, we attempt to present an overview of the current status of this fast moving field.     

Biomagnification of p, p′-DDT and Methoxychlor by Bacteria

Aerobacter aerogenes and Bacillus subtilis accumulated p, p'-DDT and methoxychlor directly from water. Uptake of both (14)C-labeled organochlorine insecticides was rapid; 80 to 90% of the 24-h residues were reached within 30 min. Total cellular residues varied linearly with concentrations of DDT and methoxychlor in water ranging from 0.5 to 5.0 mug/liter. The residue magnification factors from water were between 1,400- to 4,300-fold, but were independent of insecticide concentrations in water. When the insecticide-exposed microbial cells were washed with pesticide-free water, DDT residues were 45% in A. aerogenes and 30% in B. subtilis, whereas the methoxychlor level decreased nearly 75% in both organisms. Subsequent washing did not further reduce the insecticide residue. Autoclave-killed bacteria also rapidly adsorbed DDT and methoxychlor from water and, in some instances, residues were higher than in the living cells. Molecular polarity and lipid solubility appear to influence the retention of the organochlorine insecticides by bacterial cells.     

WITHDRAWN: Expression of p53, p63, and p73 isoforms in squamous cell carcinoma and adenocarcinoma of esophagus☆,☆☆

Diabetic microangiopathy is often observed in diabetic patients, but there is little evidence regarding the relationship between post-prandial glycemia or insulinemia and the incidence of diabetic microangiopathy. In this study, to elucidate the relationship between post-prandial glycemia (or insulinemia) and diabetic microangiopathy, we performed a cross-sectional study of 232 subjects with type 2 diabetes mellitus who were not being treated with insulin injections. A multiple regression analysis showed that post-prandial hyperglycemia independently correlated with the incidence of diabetic retinopathy and neuropathy. Post-prandial hyperglycemia also correlated, although not independently, with the incidence of diabetic nephropathy. In addition, interestingly, post-prandial hypoinsulinemia independently correlated with the incidence of diabetic retinopathy, although not correlated with diabetic neuropathy or nephropathy. In conclusion, post-prandial hyperglycemia, rather than fasting glycemia or hemoglobin A1c levels, is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients.     

Serum concentrations of TNF-α, sTNF-R p55 and p75 and post-traumatic stress in German soldiers

Growing evidence suggests involvement of the tumor necrosis factor (TNF)-α system in the pathophysiology of psychiatric disorders. Research into post-traumatic stress disorder (PTSD) has investigated serum levels of TNF-α, but not to date its soluble receptors sTNF-R p55 and sTNF-R p75. We examined serum levels of TNF-α, sTNF-R p55 and sTNF-R p75 in 135 male German soldiers 70 of whom had been deployed abroad and 65 in Germany only. Post-traumatic stress symptoms were measured using the Post-traumatic Stress Diagnostic Scale (PDS) and the Trier Inventory for the Assessment of Chronic Stress (TICS). Correlational analysis controlling for multiple testing, showed no significant Spearman rank correlations between PDS or TICS scores and serum levels of TNF-α, sTNF-R p55 or sTNF-R p75, either in the full sample or in the group of soldiers who had been deployed abroad. ANCOVAs showed no significant differences between soldiers with or without a PDS-derived diagnosis of PTSD, or between soldiers with or without deployment abroad, after controlling for age, smoking and body mass index (BMI). These results suggest that the TNF-α system, as reflected by TNF-α, sTNF-R p55 and sTNF-R p75 serum levels, does not play a major role in the pathophysiology and development of PTSD symptoms as measured by the PDS and the TICS. However, several methodological and contextual issues have to be considered.     

Are p27 and p21 Cytoplasmic Oncoproteins?

By causing cytoplasmic mislocation of p27 and p21, the Akt oncogenic kinase functionally inactivates these nuclear tumor suppressor proteins. Is cytoplasmic localization of p27 and p21 simply equivalent to loss of their function or are new functions acquired in the cytoplasm? Indeed, several lines of evidence suggest that cytoplasmic p27 and p21 may be oncoproteins with antiapoptotic activities.     

Are p27 and p21 cytoplasmic oncoproteins?

By causing cytoplasmic mislocation of p27 and p21, the Akt oncogenic kinase functionally inactivates these nuclear tumor suppressor proteins. Is cytoplasmic localization of p27 and p21 simply equivalent to loss of their function or are new functions acquired in the cytoplasm? Indeed, several lines of evidence suggest that cytoplasmic p27 and p21 may be oncoproteins with antiapoptotic activities.     

Matched work high-intensity interval and continuous running induce similar increases in PGC-1α mRNA, AMPK, p38, and p53 phosphorylation in human skeletal muscle

The aim of the present study was to test the hypothesis that acute high-intensity interval (HIT) running induces greater activation of signaling pathways associated with mitochondrial biogenesis compared with moderate-intensity continuous (CONT) running matched for work done. In a repeated-measures design, 10 active men performed two running protocols consisting of HIT [6 × 3-min at 90% maximal oxygen consumption (Vo(2max)) interspersed with 3-min recovery periods at 50% Vo(2max) with a 7-min warm-up and cool-down period at 70% Vo(2max)] or CONT (50-min continuous running at 70% Vo(2max)). Both protocols were matched, therefore, for average intensity, duration, and distance run. Muscle biopsies (vastus lateralis) were obtained preexercise, postexercise, and 3 h postexercise. Muscle glycogen decreased (P < 0.05) similarly in HIT and CONT (116 ± 11 vs. 111 ± 17 mmol/kg dry wt, respectively). Phosphorylation (P-) of p38MAPK(Thr180/Tyr182) (1.9 ± 0.1- vs. 1.5 ± 0.2-fold) and AMPK(Thr172) (1.5 ± 0.3- vs. 1.5 ± 0.1-fold) increased immediately postexercise (P < 0.05) in HIT and CONT, respectively, and returned to basal levels at 3 h postexercise. P-p53(Ser15) (HIT, 2.7 ± 0.8-fold; CONT, 2.1 ± 0.8-fold), PGC-1α mRNA (HIT, 4.2 ± 1.7-fold; CONT, 4.5 ± 0.9-fold) and HSP72 mRNA (HIT, 4.4 ± 2-fold; CONT, 3.5 ± 1-fold) all increased 3 h postexercise (P < 0.05) although neither parameter increased (P > 0.05) immediately postexercise. There was no difference between trials for any of the above signaling or gene expression responses (P > 0.05). We provide novel data by demonstrating that acute HIT and CONT running (when matched for average intensity, duration, and work done) induces similar activation of molecular signaling pathways associated with regulation of mitochondrial biogenesis. Furthermore, this is the first report of contraction-induced p53 phosphorylation in human skeletal muscle, thus highlighting an additional pathway by which exercise may initiate mitochondrial biogenesis.     

A de novo case of trisomy 10p: Gene dosage studies of hexokinase,inorganic pyrophosphatase and adenosine kinase

Summary A female infant with multiple congenital anomalies is presented. Cytogenetic study revealed the presence of a de novo, supernumerary, small telocentric chromosome exhibiting the banding pattern of the short arm of chromosome no. 10 [47,XX,+10p(ptercen)]. Her clinical features were compatible with the 10p trisomy syndrome. Hexokinase (HK-1) activity was elevated in the patient's erythrocytes, which is consistent with an assignment of HK-1 to 10ptercen10. The absence of a gene dosage effect for inorganic pyrophosphatase (PP) in this study indicates exclusion of PP from 10pter cen10, and therefore implies a regional assignment of cen1010q24 for PP. Adenosine kinase (ADK) activity was within control limits, which is consistent with exclusion of ADK from 10ptercen10.     

A deletion in chromosome 22 can cause digeorge syndrome

Summary An association between DiGeorge's syndrome and an unbalanced chromosomal rearrangement leading to trisomy 20pter20q11 and monosomy 22pter22q11 was found in four individuals belonging to one family. These and other data from the literature are interpreted to suggest that DiGeorge's syndrome can be caused by deletion of a gene located in chromosome 22, probably in band 22q11.     

A deletion panel of the long arm of the X chromosome: subregional localization of 22 DNA probes

Summary Two males and two females with different but overlapping deletions on the proximal long arm of the X chromosomes have been investigated. Their karyotypes, which have been well characterized by high resolution banding techniques, are 46,Y,del(X)(pterq21.1:: q21.33qter); 46,Y,del(X) (pterq21.2::q21.31qter); 46,X,del(X) (pterq21.31::q24.3qter) and 46,X,del (X)(pterq21.1:). A deletion panel, which makes it possible to subdivide the long arm of the X chromosome into seven subregions, has been established using the genomic DNA from the four families, and applied to the fine subregional localization of the loci for 22 DNA probes. Based on the results obtained, the possible location of the loci in question has been narrowed down considerably, in some cases to an area of only 5% of the previously assigned region; hybridization to Southern blots of a panel with well-characterized chromosome deletions is thus a powerful means of localizing DNA probes, especially with respect to the X probes.Part of the results from this investigation were published at Human Gene Mapping 9 as abstracts     

Point mutations in the upstream region of the α-galactosidase A gene exon 6 in an atypical variant of Fabry disease

Summary Single point mutations in the upstream region of exon 6 of the -galactosidase A gene were found in two Japanese cases of the cardiac form of Fabry disease; ³⁰¹ArgGln (⁹⁰²GA) in a case that has already been published and ²⁷⁹GlnGlu (⁸³⁵CG) in a new case. They both expressed markedly low, but significant, amounts of residual activity in COS-1 cells. In contrast, two unrelated cases with classic Fabry disease were found to have different point mutations, which showed a complete loss of enzyme activity in a transient expression assay; ³²⁸GlyArg (⁹⁸²GA) in the downstream region of exon 6 in one case and two combined mutations, ⁶⁶GluGln (¹⁹⁶GC)/¹¹²ArgCys (³³⁴CT), in exon 2 in the other. We conclude, on the basis of the results recorded in this study and those in previous reports, that the pathogenesis of atypical Fabry disease is closely associated with point mutations in the upstream region of exon 6 of the -galactosidase A gene.     

Possible complex translocation t(9; 14; 13)(q12;pl?;q31) in mother of a child with 9p-trisomy syndrome

Summary A mentally retarded boy with trisomy 9p is described. This trisomy arose through aberrant segregation of translocation chromosome during meiosis in his mother, who has a complex translocation involving chromosomes 9, 13, and 14. Based on both G-, Q-banding, and DNA replication patterns, the patient's karyotype was identified as 47,XY,-13, +(9;13) (9pter9q12::13q3113qter), +t(13;14) (13pter13q31::14pl?14pter). We suppose his mother's karyotype to be 46,XX,-9,-13,-14,+t(9;13) (9pterq12::13q3113qter), +t(13;14) (13pter13q31::14pl?14pter), +t(9;14) (9qter9q12::14pl?14qter). His phenotypically normal brother and sister are also carriers, having the same translocation chromosome as their mother. Clinical findings of the patient included peculiar face with hypertelorism, prominent nasal bridge and deformed helix, marked delay of osseous development, hypoplastic phalangia in fingers and toes, dysplastic nails and absence of digital triradii.     

Is There a Field-Theoretic Explanation For Precursor Biopolymers?

A Hu-Barkana-Gruzinov cold dark matter scalarfield may enter a weak isospin invariant derivative interactionthat causes the flow of right-handed electrons to align parallelto (). Hence, in the outer regions of galaxies where () islarge, as in galactic halos, the derivative interaction mayinduce a chirality-imbued quantum chemistry. Such a chirality-imbued chemistry would in turn be conducive to the formation ofabundant precursor biopolymers on interstellar dust grains,comets and meteors in galactic halo regions, with subsequentdelivery to planets in the inner galactic regions where and() are concomitantly near zero and left-right symmetricterrestrial quantum chemistry prevails.     

β-D-Glycan synthases and the CesA gene family: lessons to be learned from the mixed-linkage (1→3),(1→4)β-D-glucan synthase

Cellulose synthase genes (CesAs) encode a broad range of processive glycosyltransferases that synthesize (14)-D-glycosyl units. The proteins predicted to be encoded by these genes contain up to eight membrane-spanning domains and four `U-motifs' with conserved aspartate residues and a QxxRW motif that are essential for substrate binding and catalysis. In higher plants, the domain structure includes two plant-specific regions, one that is relatively conserved and a second, so-called `hypervariable region' (HVR). Analysis of the phylogenetic relationships among members of the CesA multi-gene families from two grass species,Oryza sativa and Zea mays, with Arabidopsis thaliana and other dicotyledonous species reveals that the CesA genes cluster into several distinct sub-classes. Whereas some sub-classes are populated by CesAs from all species, two sub-classes are populated solely by CesAs from grass species. The sub-class identity is primarily defined by the HVR, and the sequence in this region does not vary substantially among members of the same sub-class. Hence, we suggest that the region is more aptly termed a `class-specific region' (CSR). Several motifs containing cysteine, basic, acidic and aromatic residues indicate that the CSR may function in substrate binding specificity and catalysis. Similar motifs are conserved in bacterial cellulose synthases, the Dictyostelium discoideum cellulose synthase, and other processive glycosyltransferases involved in the synthesis of non-cellulosic polymers with (14)-linked backbones, including chitin, heparan, and hyaluronan. These analyses re-open the question whether all the CesA genes encode cellulose synthases or whether some of the sub-class members may encode other non-cellulosic (14)-glycan synthases in plants. For example, the mixed-linkage (13)(14)-D-glucan synthase is found specifically in grasses and possesses many features more similar to those of cellulose synthase than to those of other -linked cross-linking glycans. In this respect, the enzymatic properties of the mixed-linkage -glucan synthases not only provide special insight into the mechanisms of (14)-glycan synthesis but may also uncover the genes that encode the synthases themselves.     

Cytochrome P-450-dependent catabolism of triethanolamine in Rhodotorula mucilaginosa

The yeast Rhodotorula mucilaginosa was able to grow in media containing triethanolamine or diethanolamine as the sole nitrogen source. During growth in the presence of triethanolamine, extracts of yeast cells contained increased levels of cytochrome P-450 dependent monooxygenase which catalyzed the oxidative N-dealkylation of aminoalcohols. Formation of diethanolamine, ethanolamine and glyoxylate from triethanolamine was demonstrated, and the identity of the products was verified by thin layer chromatography. These observations suggested the following scheme of triethanolamine catabolism: triethanolamine diethanolamine + glycolaldehyde, diethanolamine ethanolamine + glycolaldehyde, ethanolamine NH₃ + glycolaldehyde glycolate glyoxylate glycerate pathway.     

Structural diversity of O-polysaccharides and serological classification of <Emphasis Type="Italic">Pseudomonas syringae</Emphasis> pv. <Emphasis Type="Italic">garcae</Emphasis> and other strains of genomospecies 4

Novel O-serotypes were revealed among Pseudomonas syringae pv. garcae strains by using a set of mouse monoclonal antibodies specific to the lipopolysaccharide O-polysaccharide. Structural studies showed that the O-polysaccharide of P. syringae pv. garcae NCPPB 2708 is a hitherto unknown linear L-rhamnan lacking strict regularity and having two oligosaccharide repeating units I and II, which differ in the position of substitution in one of the rhamnose residues and have the following structures: I:3)--L Rha (12)-- L Rha (12)--L-Rha-(13)--L Rha (1;II: 2)--L-Rha-(13) -L-Rha-(12)--L-Rha-(13)--L Rha (1.The branched O-polysaccharides of P. syringae pv. garcae ICMP 8047 and NCPPB 588^T have the same L-rhamnan backbone with repeating units I and II and a lateral chain of 14)- or 13)-linked residues of 3-acetamido-3,6-dideoxy-D-galactose (D-Fuc3NAc). Several monoclonal antibody epitopes associated with the L-rhamnan backbone or the lateral -D-Fuc3NAc residues were characterized.Translated from Mikrobiologiya, Vol. 73, No. 6, 2004, pp. 777–789.Original Russian Text Copyright © 2004 by Ovod, Zdorovenko, Shashkov, Kocharova, Knirel.     

Production of an extracellular polysaccharide byAgrobacterium sp DS3 NRRL B-14297 isolated from soil

A bacterium isolated from soil and identified asAgrobacterium sp produced a water-soluble extracellular polysaccharide capable of producing highly viscous solutions. Gas chromatographic analysis revealed a sugar composition of glucose, galactose and mannose in the molar ratio of 7.52.41, together with 3.7% (w/w) pyruvic acid. Methylation analyses showed the presence of (13)-, (14)- and (16)-linked glucose, (13)- and (14, 16)-linked galactose and a small portion of (13)-linked mannose residues. Succinic acid was not present. The molecular weight of the polysaccharide was estimated by light scattering to be 2×10⁶ Da. The viscosity of solutions containing the polysaccharide remained constant from pH 3 to 11, and decreased by 50% when heated from 5 to 55°C. Maximum yield of the polysaccharide, 20 g L^–1, was reached in 48 h at 30°C incubation.