[Functional classification of regulator peptides. Divergent and convergent evolution of regulator peptides].
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Contributions to the micro-anatomical evaluation of the ratio between the muscular tunic structures of the oesophagus. Biomechanical, anatomic and clinical implications.
The aim of our research is to make a microanatomical evaluation of the ratios of the structural elements of the oesophagus muscular tunic and suggest a new perspective in the general knowledge about this tubular organ. The visualisation of the structural elements was done using classical microanatomical methods Hematoxylin-Eosin for general orientation, Van Gieson for picrofuxinophile collagen fibers and Gömöri for reticuline fibers. The neurofilaments were identified using silver impregnation on Cajal block. The examination of the sections was made with the Nikon Eclipse 600 photomicroscope. The images were taken and processed using a computer with LuciaNet licensed Microsoft. The co-existence in the architecture of the oesophagus of two microcinematic systems structurally divergent, but functionally convergent represents microanatomical arguments for the nomination of a new type of muscles--the oesophageal muscle--anatomo-functionally different from the skeletal striate muscle, from the smooth visceral muscle, from the cardiac muscle or from the embryonic type muscle of the excitoconductor system. The extra cellular matrix of the muscular tunic of the oesophagus contributes to the organization of the endo- and peri-misium, as well as to the three structures involved in the biomechanics of the oesophageal muscle: the connective-vascular septa, the microtendons that have in their structure receptors of the peristaltic reflex and, finally, the lamina propria myenterica strewed with numerous neuronal structures. The co-existence of the stereo-distribution of the monostructured fascicles (skeletal muscular fibers or smooth muscular cells) with bistructured fascicles (skeletal-smooth) gives the oesophagus a heterogeneous architecture. Lamina propria myenterica, which realizes the border between the circular and longitudinal strata, contains two neuronal structures of its own, but anatomically inserted the neural myenteric plexus which is equivalent to the Auerbach plexus and the neuroganglion of the myenteric plexus, equivalent to the visceral neuroganglion Cajal-Retzius.
Adult↗
[Theory of mosaics of the squamous epithelium].
Formalization of existing quantitative notions on module structure of tissues and, in particular, squamous epithelium++ has been performed. An idea has been developed on the elementary tissue unit (ETU), appearing as a consequence of divergence ++ of functions among cells. The tissue is considered as a result of polymerization of the ETU. According to cell composition in the ETU, the tissues are proposed to be divided into simple and complex ones. Certain sets of rules have been formulated concerning polymerization of the ETU, they allow to find a lot of all possible constructions of simple and complex tissues and, in this way, prognosticate their development in phylo- and ontogenesis. A part of theoretically found constructions are demonstrated to be realized in some animals. New informative signs are suggested for studying tissues in normal development and in pathological conditions.
Animals↗
Light microscopical structure of the excurrent ducts and distribution of spermatozoa in the Australian rodents Pseudomys australis and Notomys alexis.
The light microscopical structure of the male excurrent ducts and the distribution of spermatozoa were examined in two species of Australian rodents, the plains rat, Pseudomys australis, and the hopping mouse, Notomys alexis. In plains rats the microstructure of the ductus epididymidis and ductus deferens was similar to that of the common laboratory rodents, with the majority of the spermatozoa being found in the cauda epididymides. By contrast, in the hopping mouse, the structure of the cauda epididymidis differed significantly as the height of the epithelium and stereocilia did not decrease from the distal caput to the cauda region, and luminal diameter did not increase markedly along its length. In addition, few spermatozoa were stored in the cauda region of the tract, and as many as 60% were located in the ductus deferens, the distal portion of which displayed a highly infolded epithelium and underlying lamina propria. These differences in histological structure of the hopping mouse excurrent ducts presumably reflect divergence in function of the various regions of the tract. Although the functional implications of the present findings remain to be determined, this study demonstrates the considerable plasticity in the male excurrent ducts amongst the hydromyine rodents of Australia.
Animals↗
Some neural and non-neural factors in visual development of the kitten.
Kittens appear visually immature at eye opening and studies were conducted to trace changes with maturity. Longitudinal determinations of optical quality indicate that optical factors may not limit visual performance in young kittens. Estimates of visual axis alignment in alert kittens at various ages show that functional visual divergence does not occur even when the pupillary axes are divergently misaligned. It is thus possible that fused binocular vision may occur in very young kittens, suggesting that procedures that disrupt binocularity may have effects at the cortical level. Single-unit analysis of striate cortex in kittens monocularly deprived for varying periods during the first three postnatal weeks confirms this possibility. Effects are also found for kittens reared with monocular defocus to simulate anisometropia. Binocular recovery from the effects of monocular deprivation is found to be quite limited in kittens given binocular exposure following unilateral lid-suture. The recovery that occurs requires active visual input rather than a cessation of imbalance in the two eyes. A long period of binocular exposure appears to be ineffective in restoring binocular connections in a cat reared with optically induced strabismus.
Animals↗
Hormonal regulation of insulin-like growth factor II and insulin-like growth factor binding protein expression by breast cancer cells in vivo: evidence for stromal epithelial interactions.
Insulin-like growth factors (IGFs) I and II are potent mitogens for breast cancer cells. Their proliferative activity is likely to be influenced by their binding proteins (IGFBPs), a family of newly identified proteins. We report here on the in vivo hormonal regulation of mRNAs for IGF-II and IGFBPs in the N-nitrosomethylurea-induced rat mammary tumor, a well-established model of hormone-responsive mammary cancer. IGF-II mRNA levels tended to decrease in regressing tumors following ovariectomy, and they markedly increased upon reactivation of tumor growth with hormone repletion. Ovariectomy induced a drastic increase in IG-FBP-6 mRNA which was reversible with hormone repletion. Similar but more modest changes were observed with IGFBP-2 mRNA. In contrast, IGFBP-3 and IGFBP-4 mRNAs tended to decrease with ovariectomy and increase with hormone repletion. These latter effects, however, were modest, variable, and not statistically significant. In situ hybridization analysis revealed that IGF-II, IGFBP-5, and IGFBP-6 mRNAs were localized in the stromal component of the tumor, whereas IGFBP-2 mRNA was expressed by epithelial cells. We conclude that hormonal regulation of IGFBP expression is heterogeneous, thus suggesting divergent biological functions for these peptides. Our data also emphasize the importance of potential stromal-epithelial interactions in the control of breast cancer cell proliferation by IGFs.
Animals↗
Establishment and molecular characterization of a novel leukemic cell line with Philadelphia chromosome expressing p230 BCR/ABL fusion protein.
The cell line AR230 was established from the peripheral blood mononuclear cells of a patient with chronic myeloid leukemia and t(9;22) translocation bearing a variant type of BCR/ABL rearrangement. AR230 expresses a BCR/ABL fusion protein with a molecular mass of 230 kilodaltons (kDa) due to the insertion of 180 amino acids encoded by 3' exons of BCR (b4 to c3). An immune complex kinase assay showed that the 230-kDa BCR/ABL protein ahd autophosphorylation activity. Immunoprecipitation analysis revealed a stable complex of GRB2 and 230-kDa BCR/ABL proteins, indicating that the Ras activation pathway is involved in the process of transformation. AR230 expressed another short transcript consisting of a BCRc2/ABL junction, which is associated with a stop signal shortly after the junction. To our knowledge, this is the first cell line expressing a 230-kDa fusion product of BCR/ABL. AR230 will be useful for studying the biological function of divergent BCR/ABL proteins.
Amino Acid Sequence↗
Small-cell carcinoma combined with adenocarcinoma of the gallbladder. A case report with immunohistochemical and flow cytometric studies.
A small-cell carcinoma combined with adenocarcinoma of the gallbladder was detected in a 71-year-old Japanese woman. A nodular mass measuring 4.0 x 5.0 cm was located in the fundus of the gallbladder, in which a tiny depressed lesion measuring 2 mm in diameter was macroscopically and stereomicroscopically observed. Histologically, the depressed area revealed small-cell carcinoma that consisted of atypical cells with small, round to oval nuclei and scanty cytoplasm and was surrounded by ordinary well-differentiated adenocarcinoma. Immunohistochemically, the tumor cells in an adenocarcinomatous area were diffusely positive for carcinoembryonic antigen and showed an interspersed positivity to serotonin and gastrin, while the tumor cells in the small-cell carcinoma area were negative for both antigens. The nuclear DNA content of the tumor cells of both components was aneuploid; however, the first G0/G1 peak of the small-cell carcinoma was much smaller than that of the adenocarcinoma. These results indicated that the tumor revealed a divergence in functional differentiation, and this feature suggested an initial phase of composite small-cell carcinoma and adenocarcinoma in the gallbladder.
Adenocarcinoma↗
Response of cultured cells from the epidermis and the buccal mucosa to TGF-beta 1 and comparison to interferon-gamma.
Normal human cells from epidermis and from buccal mucosa were cultured to confluence in three media with graded differentiation potential (at low Ca2+, high Ca2+, and supplemented with serum) and treated with transforming growth factor beta 1 (TGF-beta 1), as had been done previously with interferon-gamma (IFN-gamma). The response of the cells to TGF-beta 1 was monitored in terms of the expression of regulatory genes associated with proliferation and differentiation (cdc2, c-myc, p53) and of genes for structural proteins expressed at varying stages of maturation (keratins K5 and K10, involucrin, flaggrin). For both tissues, the results obtained with both agents were very similar for those genes expressed in the basal cells (cdc2, c-myc, p53, K5), regardless of their function, but diverged for the other genes, which are expressed in the suprabasal cells. Another related contrast is that, although IFN-gamma induced apoptosis in epidermal keratinocytes cultured in the serum containing medium, TGF-beta 1 did not. Thus, the two agents appear to affect the earlier stages of cell differentiation in the same way but to differ at the later stages, particularly in that IFN-gamma pushes maturation further than does TGF-beta 1).
CDC2 Protein Kinase↗
Characterisation of a human endometrial adenocarcinoma established in vivo and in vitro.
A moderately differentiated human endometrial adenocarcinoma was heterotransplanted into nude mice and later established as a continuous in vitro cell line. Western blot analysis showed an accumulation of p53 protein in the cell line compared to the original tumour and heterotransplants. Sequential analysis of the p53 gene revealed point mutations in codons 175 and 248 in the cell line while no mutations were found prior to in vitro establishment. Immunohistochemistry confirmed the epithelial origin of the heterotransplants and of retransplants of the cell line. The intraperitoneal retransplants remained moderately differentiated, whereas subcutaneous retransplants became less differentiated. Heterotransplants were estrogen receptor (ER) positive and progesterone receptor (PgR) negative, indicating preservation of normal steroid receptor status. The ER could not be detected in the in vitro cell line using an enzyme immunoassay, but was detected with Western blot using a polyclonal antibody toward the carboxy terminus. After estradiol treatment, the in vitro cell line became weakly positive for the PgR, suggesting the ER mechanism was at least partly intact. Tumour growth in vivo was independent of endogenous estrogen but was inhibited when the tumour-bearing animals were treated with estradiol. Analysis of cell growth kinetics by flow cytometry (FCM) after bromodeoxyuridine (BrdU)-labelling revealed no difference in S-phase fraction (SPF) or labelling index (LI) between the treated and control groups. Cell loss (CL) was significantly increased from 42% to 89%, resulting in increased tumour volume doubling time (TVDT). Under in vitro conditions estradiol treatment resulted in an increase in cell doubling time and this growth retardation was accompanied by a significant decrease in SPF and LI. The estrogen responsive (inhibited) phenotype was thus preserved in the in vitro cell line but was probably mediated through another mechanism. This cell line thus appears to represent the development of a more malignant clone with divergent receptor function and growth behaviour, and provides us with an interesting new tool for the study of tumorigenesis in the human endometrium.
Adenocarcinoma↗
Neuronal function in chronic spinal cord injury: divergence between locomotor and flexion- and H-reflex activity.
OBJECTIVE: Knowledge about the long-term course of spinal neuronal function after spinal cord injury (SCI) is important if regeneration therapies become available in the future. The objective of this study was to examine the behavior of locomotor EMG activity and of spinal reflexes in patients with chronic motor-complete SCI. METHODS: EMG activity from rectus femoris (RF), biceps femoris (BF), medial gastrocnemius (GM) and tibialis anterior (TA) of both sides was investigated during locomotor movements assisted by a robotic device in 10 chronic (>1 year after accident) complete SCI and 5 healthy subjects. H-reflexes (recorded from GM) were induced during the onset and flexion reflexes (recorded from BF and TA) at the end of the stance phase. RESULTS: Only in the chronic SCI subjects an exhaustion of EMG activity--i.e. a decrease in amplitude--occurred within a few minutes in all leg muscles. The EMG exhaustion was not associated with a change in the H- or flexion reflex amplitude during a walking session. CONCLUSIONS: Exhaustion of neuronal function in chronic complete SCI might be restricted to unused motor tasks, i.e. locomotion. The fact that H- and flexion reflexes show a normal behavior might be due to the fact that they still become activated. SIGNIFICANCE: Training/pharmalogical approaches may be required to maintain neuronal function of unused tasks as a basis for future successful regeneration therapies.
Adult↗
The presence but not the sequence of the N-terminal peptide in cardiac TnC is important for function.
The most diverged region of the primary amino acid sequence between cardiac (cTnC) and fast skeletal troponin C is the N-terminal ten amino acids. We report here that major changes in the primary sequence of this region in cTnC had a minimal effect on the ability of the mutant proteins to recover maximal activity in TnC-extracted cardiac and fast skeletal muscle myofibrils. However, deletion of the N-terminal nine amino acids resulted in a 60% decrease in maximal Ca(2+)-dependent ATPase activity with only a small change in the pCa50 of activation. Deletion of the N-terminal peptide did not appear to appreciably affect the Ca(2+)-binding properties of cTnC, but it did alter the interaction with hydrophobic fluorescent probes. Thus, the presence but not the sequence, of the N-terminal extension is important for the maximal activity of cTnC. The N-terminal helix may function in a relatively non-specific manner to prevent unfavorable interactions between domains in cTnC or between cTnC and other troponin subunits.
Adenosine Triphosphatases↗
Evolution of sex determination in caenorhabditis: unusually high divergence of tra-1 and its functional consequences.
The tra-1 gene is a terminal regulator of somatic sex in Caenorhabditis elegans: high tra-1 activity elicits female development, low tra-1 activity elicits male development. To investigate the function and evolution of tra-1, we examined the tra-1 gene from the closely related nematode C. briggsae. Ce-tra-1 and Cb-tra-1 are unusually divergent. Each gene generates two transcripts, but only one of these is present in both species. This common transcript encodes TRA-1A, which shows only 44% amino acid identity between the species, a figure much lower than that for previously compared genes. A Cb-tra-1 transgene rescues many tissues of tra-1(null) mutants of C. elegans but not the somatic gonad or germ line. This transgene also causes nongonadal feminization of XO animals, indicating incorrect sexual regulation. Alignment of Ce-TRA-1A and Cb-TRA-1A defines several conserved regions likely to be important for tra-1 function. The phenotypic differences between Ce-tra-1(null) mutants rescued by Cb-tra-1 transgenes and wild-type C. elegans indicate significant divergence of regulatory regions. These molecular and functional studies suggest that evolution of sex determination in nematodes is rapid and genetically complex.
Amino Acid Sequence↗
Cloning and characterization of a FLORICAULA/LEAFY ortholog, PFL, in polygamous papaya.
The homologous genes Floricaula (FLO) in Antirrhinum and LEAFY (LFY) in Arabidopsis are known to regulate the initiation of flowering in these two distantly related plant species. These genes are necessary also for the expression of downstream genes that control floral organ identity. We used Arabidopsis LFY cDNA as a probe to clone and sequence a papaya ortholog of LFY, PFL. It encodes a protein that shares 61% identity with the Arabidopsis LFY gene and 71% identity with the LFY homologs of the two woody tree species: California sycamore (Platanus racemosa) and black cottonwood (Populus trichocarpa). Despite the high sequence similarity within two conserved regions, the N-terminal proline-rich motif in papaya PFL differs from other members in the family. This difference may not affect the gene function of papaya PFL, since an equally divergent but a functional LFY ortholog Needly of Pinus radiata has been reported. Genomic and BAC Southern analyses indicated that there is only one copy of PFL in the papaya genome. In situ hybridization experiments demonstrated that PFL is expressed at a relatively low level in leaf primordia, but it is expressed at a high level in the floral meristem. Quantitative PCR analyses revealed that PFL was expressed in flower buds of all three sex types - male, female, and hermaphrodite with marginal difference between hermaphrodite and unisexual flowers. These data suggest that PFL may play a similar role as LFY in flower development and has limited effect on sex differentiation in papaya.
Amino Acid Sequence↗
In vivo coassembly of a divergent beta-tubulin subunit (c beta 6) into microtubules of different function.
alpha- and beta-Tubulin are encoded in vertebrate genomes by a family of approximately 6-7 functional genes whose polypeptide products differ in amino acid sequence. In the chicken, one beta-tubulin isotype (c beta 6) has previously been found to be expressed only in thrombocytes and erythroid cells, where it is assembled into a circumferential ring of marginal band microtubules. In light of its unique in vivo utilization and its divergent assembly properties in vitro, we used DNA transfection to test whether this isotype could be assembled in vivo into microtubules of divergent functions. Using an antibody specific to c beta 6, we have found that upon transfection this polypeptide is freely coassembled into an extensive array of interphase cytoplasmic microtubules and into astral and pole-to-chromosome or pole-to-pole microtubules during mitosis. Further, examination of developing chicken erythrocytes reveals that both beta-tubulins that are expressed in these cells (c beta 6 and c beta 3) are found as co-polymers of the two isoforms. These results, in conjunction with efforts that have localized various other beta-tubulin isotypes, demonstrate that to the resolution limit afforded by light microscopy in vivo microtubules in vertebrates are random copolymers of available isotypes. Although these findings are consistent with functional interchangeability of beta-tubulin isotypes, we have also found that in vivo microtubules enriched in c beta 3 polypeptides are more sensitive to cold depolymerization than those enriched in c beta 6. This differential quantitative utilization of the two endogenous isotypes documents that some in vivo functional differences between isotypes do exist.
Amino Acid Sequence↗
Efficient transcription of a Caenorhabditis elegans heat shock gene pair in mouse fibroblasts is dependent on multiple promoter elements which can function bidirectionally.
A divergently transcribed pair of Caenorhabditis elegans hsp16 genes was introduced into mouse fibroblasts by stable transfection with vectors containing bovine papillomavirus plasmid maintenance sequences and a selectable gene. The hsp16 genes were transcriptionally inactive in the mouse cells under normal growth conditions and were strongly induced by heat shock or arsenite. In a cell line with 12 copies of the gene pair, there were estimated to be more than 10,000 hsp16 transcripts in each cell after 2 h of heat shock treatment. The hsp16 transcript levels were more than 100 times higher than those of a gene with a herpes simplex virus thymidine kinase gene promoter carried on the same vector. A single heat shock promoter element (HSE) could activate bidirectional transcription of the two hsp16 genes when placed between the two TATA elements, but the transcriptional efficiency was reduced 10-fold relative to that of the wild-type gene pair. Four overlapping HSEs positioned between the two TATA elements resulted in inducible bidirectional transcription at greater than wild-type levels. The number of HSEs can therefore be a major determinant of the promoter strength of heat-inducible genes in mammalian cells. Partial disruption of an alternating purine-pyrimidine sequence between the two hsp16 genes had no significant effect on their transcriptional activity.
Animals↗
Sequence and structural aspects of functional diversification in class I alpha-mannosidase evolution.
MOTIVATION: Class I alpha-mannosidases comprise a homologous and functionally diverse family of glycoside hydrolases. Phylogenetic analysis based on an amino acid sequence alignment of the catalytic domain of class I alpha-mannosidases reveals four well-supported phylogenetic groups within this family. These groups include a number of paralogous members generated by gene duplications that occurred as far back as the initial divergence of the crown-group of eukaryotes. Three of the four phylogenetic groups consist of enzymes that have group-specific biochemical specificity and/or sites of activity. An attempt has been made to uncover the role that natural selection played in the sequence and structural divergence between the phylogenetically and functionally distinct Endoplasmic Reticulum (ER) and Golgi apparatus groups. RESULTS: Comparison of site-specific amino acid variability profiles for the ER and Golgi groups revealed statistically significant evidence for functional diversification at the sequence level and indicated a number of residues that are most likely to have played a role in the functional divergence between the two groups. The majority of these sites appear to contain residues that have been fixed within one organelle-specific group by positive selection. Somewhat surprisingly these selected residues map to the periphery of the alpha-mannosidase catalytic domain tertiary structure. Changes in these peripherally located residues would not seem to have a gross effect on protein function. Thus diversifying selection between the two groups may have acted in a gradual manner consistent with the Darwinian model of natural selection. CONTACT: bishogr@millsaps.edu.
Amino Acid Sequence↗
Surface map comparison: studying function diversity of homologous proteins.
A simplified protein surface cartography approach has been developed to assist in the analysis of surface features in homologous families, and thus to predict conservation or divergence of protein functions and protein-protein interaction patterns. A spherical approximation of protein surface was used, with a focus on charged and hydrophobic residues. The resulting surface map allows for qualitative analysis and comparison of surfaces of proteins, but can also be used to define a simple numerical measure of map similarity between two or more proteins. The latter was shown to be useful for function based classifications within large protein families. Surface map analysis was tested on several test cases: haemoglobins, death domains and TRAF domains. It was shown that surface map comparison allows a better function prediction than general sequence analysis methods and can reproduce known examples of functional variation within a divergent group of proteins. In another example, we predict novel, unexpected sets of common functional properties for seemingly distant members of a large group of divergent proteins. The method was also shown to be robust enough to allow using protein models from comparative modelling instead of experimental structures.
Animals↗