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At least 703 records · Page 39Linked to original sources
PubMed1995

Constitutively active MAP kinase kinase (MEK1) stimulates SAP kinase and c-Jun transcriptional activity in U937 human leukemic cells.

Treatment of U937 human leukemic cells with the phorbol ester PMA, activates both mitogen-activated protein kinase (MAPK) and stress-activated protein kinase (SAPK), stimulates c-Jun phosphorylation and transcriptional activity, and induces a macrophage-like differentiation of U937 cells. The involvement of the MAPK pathway in mediating both the early phosphorylation and transcriptional activation events and the chronic differentiation of U937 cells was examined utilizing constitutively active MAPK kinase (MEK1) mutants. Transient expression of an activated MEK1 construct in U937 cells was found to stimulate MAPK and SAPK activity, as well as enhancing AP1-, SRE- and c-Jun-mediated transcriptional activity. Transient transfection of MAPK phosphatase-1 (MKP-1), a protein phosphatase which preferentially dephosphorylates and inactivates MAPK, inhibited the functional effects of both PMA and the constitutively active MEK1 mutants. To determine whether specific activation of the MEK/MAPK pathway was sufficient to induce hematopoietic differentiation, U937 cell lines were established that conditionally expressed the activated MEK1 mutant under the control of the human IIa metallothionein promoter. The induction of constitutively active MEK1 protein expression resulted in an increase in MEK1 activity, c-Jun and AP-1 transcriptional activity and an inhibition of U937 cell growth. However, this growth inhibition was not accompanied by U937 cell differentiation. These results suggest that a cross-talk mechanism exists between the MAPK and SAPK signal transduction pathways in U937 cells and that PMA-mediated SAPK activation may involve the MAPK pathway. Furthermore, selective activation of the MEK/MAPK pathway utilizing a constitutively active MEK1 mutant, while growth inhibitory, was not sufficient to induce the macrophage-like differentiation of U937 cells.

Animals↗
PubMed1995

[Identification of the breakpoint-flanking markers on chromosomes 1 and 17 of a constitutional translocation T(1;17)(P36;Q12-21) in a patient with neuroblastoma].

Neuroblastoma is a childhood cancer which originates in the embryonic tissue of the developing sympathetic neural crest. In 1972, Dr. A. Knudson hypothesised a similar 'two-hit mutation' model for the origin of neuroblastoma as for retinoblastoma and Wilms tumor. In this model, malignant cell growth is caused by mutations of both alleles of a tumor suppressor gene. In hereditary tumors, a germinal mutation is present in all cells of the individual, a mutation of the remaining allele by a somatic hit causes loss of gene function. Sporadic tumors result from two somatic mutations of a tumor suppressor gene involving both alleles within the same cell. The occurrence of patients with a constitutional chromosomal deletion syndrome in association with tumor facilitated the cloning of a retinoblastoma gene and of a Wilms tumor suppressor gene. In neuroblastoma, cytogenetic and molecular studies suggest the existence of a neuroblastoma (suppressor) gene at chromosome 1, at subband 1p36. A constitutional chromosomal deletion syndrome was not known for neuroblastoma. We described a constitutional chromosome translocation t(1;17)(p36.31-21; q11.2-12) in a patient with neuroblastoma. We hypothesised that this translocation, involving the chromosomal band 1p36, predisposed the patient to neuroblastoma development by disturbance of a gene located at the translocation breakpoint. Consequently, identification of the breakpoint flanking markers can be an important step towards the identification and cloning of a neuroblastoma suppressor gene. Radioactive in situ hybridization methods were first applied on the patient's fibroblasts. Soon it became evident that cells with better growth characteristics were needed and that the availability of sufficient patient material was essential. Therefore a somatic cell fusion experiment was performed between the patient's fibroblasts and a thymidine kinase-deficient Chinese hamster cell line. Somatic cell hybrid clones were selected on the presence of the derivative human chromosomes 1 and 17, and of the normal homologues. With the use of fluorescence in situ hybridisation (FISH), the position of chromosome 1 and chromosome 17 markers respective to the breakpoints was determined on chromosome metaphases of the hybrid cell lines containing the human derivative chromosomes. The pronatriodilatine (PND) and the adenovirus 12 modification site (A12M2) were identified as distal and proximal 'single copy' flanking markers of the chromosome 1 breakpoint, respectively. The chromosomal break occurred in a highly repetitive region containing an adenovirus modification site and genes encoding transfer RNA and small U1-RNA genes. The breakpoint on chromosome 17 is located in a region with as proximal boundary the distal part of the neurofibromatosis 1 (NF1) gene locus and as distal flanking marker the SCYA7 locus, encoding the monocyte chemotactic protein-3. Southern blot analysis showed no rearrangements of hybrid DNA using single copy probes for the four flanking markers. Identification of the four breakpoint flanking markers on chromosomes 1 and 17 constitutes a pivotal step for the cloning of the translocation breakpoints and for the identification of a presumed neuroblastoma suppressor gene.

Abdominal Neoplasms↗
PubMed1996

Adjacent, cooperative elements form a strong, constitutive enhancer in the human granulocyte-macrophage colony-stimulating factor gene.

Both copies of a repeated sequence CATT(A/T), located between bp -53 and -39 in the upstream region of the human GM-CSF gene, are required for mitogen-inducible promoter activity in T lymphocytes. However, the proteins that recognize this region of the granulocyte-macrophage colony-stimulating factor (GM-CSF) promoter, and are responsible for its transcriptional regulatory activity, have not been clearly identified. Using transient transfection assays, we demonstrate that a 19-bp oligonucleotide containing the CATT(A/T) repeats has strong constitutive enhancer activity in both T cell and non-T-cell lines, even though GM-CSF is not normally constitutively expressed by these cells. A 12-bp oligonucleotide, containing only the sequence CATTAATCATTT, lacks enhancer activity indicating that the nucleotides surrounding these sequences are critical for this enhancer activity. The sequence TTTCCT, which can bind members of the ets family of transcription factors, is located just 3' of these CATT(A/T) repeats, and mutagenesis of the CCT sequence abolishes (1) the constitutive (and mitogen inducible) enhancer activity of the 19-bp GM-CSF sequences, (2) the responsiveness to transactivation by ets-1, and (3) the ability to specifically bind ets-1 and elf-1 in electrophoretic mobility shift assays (EMSA). We demonstrate that although T cells contain nuclear proteins capable of independently recognizing the ets binding site and the CATT(A/T) repeats in EMSAs, both of these regulatory elements are required for enhancer function. The strong constitutive activity of this 19-bp region suggests that negative regulation of the GM-CSF promoter is critical for the restricted expression pattern of GM-CSF mRNA.

Base Sequence↗
PubMed1996

c-kit ligand stimulates tyrosine phosphorylation of a similar pattern of phosphotyrosyl proteins in primary primitive normal hematopoietic progenitors that are constitutively phosphorylated in comparable primitive progenitors in chronic phase chronic myelogenous leukemia.

Characteristic of Philadelphia (Ph)+ chronic myelogenous leukemia (CML) is the presence of the chimeric BCR/ABL (p210) protein possessing elevated protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Our previous studies demonstrated subtle differences in the growth, phenotypic and morphologic characteristics of the most primitive subpopulations of primary lin-Ph+ chronic phase CML blasts and comparable primary lin- normal blasts. Recently, in comparing proteins phosphorylated on tyrosine in these cell populations, we reported a prominent 62 kDa phosphotyrosyl (P-tyr) protein constitutively present in primary primitive lin- CML chronic phase blasts which was virtually undetectable in primary primitive lin- normal blasts. In the present studies, we demonstrate that this P-tyr p62 from primary primitive lin- chronic phase CML blasts co-immunoprecipitates with ras-GAP. Furthermore, in addition to the p210 protein, we show in whole cell lysates the presence of other clearly consistent but less prominent P-tyr proteins with molecular weights of approximately 155, 140, 110, 55 and 45 kDa as well as more minor P-tyr proteins of approximately 190, 85, 52, 42 and 39 kDa constitutively present in primary primitive lin- chronic phase CML blasts. In analyzing proteins tyrosine phosphorylated in primary primitive lin- normal blasts in response to various hematopoietic growth factors, we found a striking similarity in the phosphorylation of four major (approximately 140, 110, 62 and 56 kDa) and three minor (approximately 51, 45 and 42 kDa) P-tyr proteins after stimulation with c-kit ligand and the P-tyr proteins constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other growth factors tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand and EPO) were much less active or stimulated phosphorylation of other proteins. It is provocative that at least seven proteins rapidly and transiently phosphorylated on tyrosine in the c-kit ligand signal transduction pathway in lin- normal blasts may be constitutive substrates for the p210 activated tyrosine kinase in comparable lin- chronic phase CML blasts. In addition, it is intriguing that some of the biological effects on hematopoietic progenitors attributed to the c-kit ligand may be similar to some of the observed biological consequences of the p210 protein, including survival and expansion of a more mature stem cell population, probably at the time of lineage commitment rather than at the level of the earliest self-renewing stem cell.

Cell Lineage↗
PubMed1996

Phosphatidylinositol 3-kinase recruitment by p185erbB-2 and erbB-3 is potently induced by neu differentiation factor/heregulin during mitogenesis and is constitutively elevated in growth factor-independent breast carcinoma cells with c-erbB-2 gene amplification.

Amplification and overexpression of the c-erbB-2 gene in 21MT-2 and 21MT-1 human breast carcinoma cells results in progressively elevated levels of constitutively tyrosine-phosphorylated p185erbB-2 and is associated with progressive insulin-like growth factor (IGF) and combined IGF/epidermal growth factor (EGF) independence in culture. In addition, the neu differentiation factor/heregulins (HRGs), a family of ligands that activate p185erbB-2 through direct binding to erbB-3 or erbB-4, are potent mitogens for various nonneoplastic mammary epithelial cells and carcinoma cell lines in the absence of both IGF and EGF in culture. We have investigated the ability of ligand induction with HRGs or the constitutive activation of p185erbB-2 in the 21MT breast carcinoma cells to induced the recruitment of phosphatidylinositol 3-kinase (PI3K) by p185erbB-2 and erbB-3. HRG was found to potently induce the recruitment of the M(r) 85,000 regulatory subunit of PI3K by phosphotyrosine proteins in both nonneoplastic H16N-2 mammary epithelial cells (which express normal c-erbB-2 levels) and in the 21MT-2 and 21MT-1 cell lines, which were all isolated from a single patient with intraductal and invasive ductal carcinoma of the breast and express c-erbB-3 but not c-erbB-4 in culture. The activation of PI3K in these cells was also associated with high-level mitogenic responsiveness to HRG, as well as the IGF/EGF-independent proliferation of the 21MT cell lines in culture. The recruitment of PI3K by phosphotyrosine protein during ligand-induced activation, or that seen constitutively in the 21MT tumor cells, did not involve detectable tyrosine phosphorylation of p85. The HRG-induced recruitment of p85 and the constitutive recruitment of p85 in the 21MT cell lines involved direct association with both p185erbB-2 and erbB-3, although greater levels were recruited directly by erbB-3. Wortmannin, a potent inhibitor of PI3K enzymatic activity, also blocked the autonomous proliferation of the 21MT cells, and this effect was reversible in long-term cultures. These data indicate that PI3K may be an especially important mediator of HRG-induced proliferation in mammary epithelial cells and is involved in the autonomous proliferation of growth factor-independent breast carcinoma cells with c-erbB-2 gene amplification.

Androstadienes↗
PubMed1996

Unique signal transduction of Eyk: constitutive stimulation of the JAK-STAT pathway by an oncogenic receptor-type tyrosine kinase.

The proto-oncogene c-eyk, the cellular counterpart of a transforming oncogene, v-eyk, encodes a receptor protein tyrosine kinase with a distinctive extracellular region. We now demonstrate that c-Eyk can be constitutively activated through dimerization, and that the active Eyk displays a unique signaling pattern. When the kinase domain of c-Eyk was fused to the extracellular and transmembrane domains of CD8, the resulting chimera showed elevated kinase activity and caused cellular transformation. We found that the activated Eyk kinases, both v- and c-Eyk, constitutively stimulate the JAK-STAT pathway, while exerting little effect on other signaling routes such as the Ras-MAP kinase and the JNK pathways. The activated Eyk kinases specifically stimulate tyrosine phosphorylation of STAT1, STAT3 and JAK1. These downstream molecules also co-immunoprecipitate with the constitutively dimerized form of Eyk. The Eyk kinase activity is required for STAT1 stimulation. We found that the activation of STAT1 but not STAT3 correlates well with cellular transformation. In constitutively stimulating the JAK-STAT pathway, particularly STAT1, Eyk is unique in its downstream signaling and may be dependent on this pathway for cellular transformation.

Animals↗
PubMed1996

Constitutive and inducible mechanisms for synthesis and release of cytokines in immune cell lines.

We found that production and release of two functionally antagonistic cytokines, TGF-beta and TNF-alpha, were regulated differently in the mast cell, T cell, and macrophage cell lines RBL-2H3, MLA-144, and U-937, respectively. TGF-beta was produced and released constitutively in all three cell lines. When, however, the cell lines were stimulated with Ag, LPS, or calcium ionophore plus PMA, acceleration of release and some additional production of TGF-beta were apparent. In contrast, TNF-alpha was produced and released only when these lines were stimulated. Although neither the glucocorticoid, dexamethasone, nor the protein kinase C inhibitor, Ro31-7549, suppressed constitutive production or release of TGF-beta, these agents inhibited TNF-alpha production and the inducible component of TGF-beta production noted above. The release of these cytokines, whether constitutive or inducible, was dependent on Golgi-processing as indicated by inhibition with brefeldin A. Therefore, although both types of cytokines were processed by Golgi, only TNF-alpha and the inducible component of TGF-beta production were protein kinase C or steroid-regulated processes. These findings suggested that constitutive and inducible pathways exist for production and release of cytokines and that the inducible pathways can be selectively suppressed by pharmacologic agents.

Animals↗
PubMed1997

Modifications of the hepatocyte growth factor/c-met pathway by constitutive expression of transforming growth factor-alpha in rat liver epithelial cells.

We have previously shown that rat liver epithelial cells (RLEC) transfected with and constitutively expressing transforming growth factor-alpha (TGF-alpha) have an enhanced mitogenic response to hepatocyte growth factor (HGF). In the study reported here, we examined tumor clones derived from the TGF-alpha transfectants with respect to mitogenic response to HGF. Tumor cell lines that expressed TGF-alpha responded to HGF with a greater increase in DNA synthesis than did the nontransfected parental RLEC (pRLEC). The tumor clones had also acquired a lower threshold for HGF response, which enabled them to undergo significant DNA synthesis at a low concentration of HGF that did not evoke a response in the pRLEC or TGF-alpha transfectants. We investigated the mechanisms by which TGF-alpha expression may influence the HGF/c-met pathway. We showed that most TGF-alpha transfectants and tumor cells displayed increases in c-met mRNA and protein, indicating that the enhanced HGF response may be due in part to an increase in the amount of receptor present. However, in all transfectants and tumor clones that constitutively expressed TGF-alpha, c-met was tyrosine phosphorylated in the absence of ligand (HGF) or other exogenous growth factors. These data suggest that induction of c-met mRNA and transactivation of c-met may be a sequela of the constitutive expression of TGF-alpha and that constitutive activation of the epidermal growth factor receptor pathway leads to phosphorylation and activation of c-met. These studies provide evidence for a novel mechanism of communication between epidermal growth factor receptor and c-met pathways that may partially explain the synergistic effects reported between TGF-alpha and HGF.

Animals↗
PubMed1997

Constitutive activation of Stat-related DNA-binding proteins in erythroid cells by the Friend spleen focus-forming virus.

The erythroleukemia-inducing Friend spleen focus-forming virus (SFFV) encodes a unique envelope glycoprotein which allows erythroid cells to proliferate and differentiate in the absence of the erythroid hormone erythropoietin (Epo). In an attempt to understand how the virus alters the growth of erythroid cells, studies were carried out to determine if virus infection leads to the constitutive activation of the Jak-Stat pathway, one of the signal transduction pathways activated by Epo. Our data indicates that expression of SFFV in erythroid cells leads to the constitutive activation of the same Stat proteins that are transiently activated by Epo. While constitutive activation of Stat proteins by SFFV is associated with Epo-independent proliferation of splenic erythroid progenitor cells from Fv-2-sensitive mice and Epo-dependent HCD-57 cells, it is not sufficient to induce their differentiation. Although constitutive activation of the same Stat proteins is detected in erythroid cells from SFFV-infected Fv-2-resistant mice, it does not lead to their Epo-independent growth. It is also not required for transformation of erythroid cells by SFFV. Studies are in progress to identify the mechanism by which Stat proteins are phosphorylated in SFFV-infected cells in the absence of Epo. Although it has been shown that Epo activates Stat proteins through Jak2 kinase, our results suggest that the SFFV-induced Stat protein activation is Jak2-independent.

Animals↗
PubMed1997

Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients.

An important step in the oncogenic transformation of hemopoietic cells and the subsequent development of leukemia is the proliferation of tumor cells in the absence of exogenous growth factors. In most cases of chronic myelocytic leukemia and in some cases of acute myelocytic leukemia and acute lymphocytic leukemia, the bcr-abl oncogene is involved in this process. Although the BCR-Abl oncoprotein demonstrates enhanced tyrosine kinase activity in leukemic cells, the mechanism by which this leads to growth factor independence remains poorly defined. One proposed mechanism is the activation of cytokine signal transduction pathways, possibly by an autocrine loop involving IL-3 and/or granulocyte-macrophage CSF. Examination of several different cell lines expressing BCR-Abl demonstrates that some of these cells have constitutive activation of the JAK/STAT signaling pathway. We have found the constitutive activation of STAT5 in most, but not all, cell lines expressing BCR-Abl. This constitutive activation of STAT5 is variably associated with a corresponding activation of JAK kinases. Ab blocking studies show that the activation of STAT5 in these cell lines cannot be attributed to the activation of an IL-3/granulocyte-macrophage CSF-driven autocrine loop. Interestingly, samples of peripheral blood cells derived from patients with acute myelocytic leukemia and chronic myelocytic leukemia, which express BCR-Abl, demonstrate constitutive activation of STAT family members. These studies suggest that in a variety of leukemic states, BCR-Abl may use a bypass mechanism to activate cytokine signal transduction pathways.

Animals↗
PubMed1997

Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells.

Signal transducers and activators of transcription (STATs) were originally identified as key components of signaling pathways involved in mediating responses to IFNs. Previous studies showed that the Src oncoprotein constitutively activates one STAT family member, Stat3. In this study, we investigated STAT activation in a panel of rodent fibroblast cell lines stably transformed by diverse viral oncoproteins. Using a temperature-sensitive mutant of v-Src, we determined that Stat3 is activated within 15 min of shift from nonpermissive to permissive temperature for cell transformation. This finding indicates that v-Src tyrosine kinase activity is required for Stat3 activation and suggests that Stat3 is proximal to signaling initiated by Src. In addition, Stat3 activation is induced by another nonreceptor tyrosine kinase, v-Fps; by polyoma virus middle T antigen, which activates Src family kinases; and by v-Sis, which acts as a ligand for the platelet-derived growth factor receptor. In contrast SV40 large T antigen, which transforms cells through different mechanisms, and the v-Ras and v-Raf oncoproteins, which lie in signaling pathways downstream of tyrosine kinases, do not activate Stat3. We did not detect significant activation of Stat1, Stat5, or Stat6 in fibroblasts transformed by the viral oncoproteins investigated. Moreover, Stat3 is activated in response to epidermal growth factor (EGF) but not heregulins in immortalized normal human breast epithelial cells. Because constitutive activation of c-Src and EGF receptor kinases is associated with the progression of breast cancer, we examined activation of STATs in human cell lines derived from breast carcinomas. We detected constitutive activation of Stat3 in five of nine breast carcinoma cell lines but not in normal breast epithelial cells. Furthermore, experiments with an EGF receptor-specific inhibitor indicated that the constitutive activation of Stat3 in these breast carcinoma cell lines is not necessarily dependent on signaling through the EGF receptor, although EGF stimulation further increases Stat3 activation. Taken together, our results demonstrate that selective activation of Stat3 is a common event during oncogenic transformation that directly or indirectly involves activation of specific tyrosine kinase signaling pathways.

3T3 Cells↗
PubMed1998

The presence of a constitutively active phosphoinositide 3-kinase in small cell lung cancer cells mediates anchorage-independent proliferation via a protein kinase B and p70s6k-dependent pathway.

Small cell lung cancer (SCLC) is characterized by early and widespread metastases. Anchorage-independent growth is pivotal to the ability of tumor cells to survive and metastasize in vivo and, under in vitro conditions, allows transformed cells to form colonies in semisolid medium. Here, we report that of five SCLC cell lines tested, all exhibited high basal constitutive phosphoinositide 3-kinase (PI 3-kinase) activity, which results in high basal protein kinase B (PKB) and ribosomal p70 S6 kinase activity (p70s6k). Inhibition of PI 3-kinase activity markedly inhibited SCLC cell proliferation in liquid culture as a result of stimulating apoptosis and promoting cell cycle delay in G1. Furthermore, PI 3-kinase inhibition reduced basal SCLC cell colony formation in agarose semisolid medium that could not be overcome by the addition of neuropeptide growth factors. Thus, constitutive PI 3-kinase activity in SCLC cells plays an important role in promoting the growth and anchorage independence of SCLC. This is not due to activating ras mutations or increased basal src or focal adhesion kinase activity. These data represent the first description of constitutively activated PI 3-kinase/PKB in any human cancer. Constitutive activation of these integrin-dependent signaling events provides a molecular explanation for the anchorage-independent growth of SCLC cells and may account for the nonadherent phenotype and highly metastatic nature of this aggressive cancer. Up-regulation of the PI 3-kinase/PKB pathway may, therefore, represent a novel target for therapeutic intervention in SCLC.

Androstadienes↗
PubMed1998

Constitutive secretion of kallikreins in vivo from rat submandibular glands.

In parasympathetic saliva from rat submandibular glands the relative proportions of the various tissue kallikreins differ from those in sympathetic saliva. Kallikreins in sympathetic saliva arise from exocytosis of prepackaged granules in granular tubules, so the kallikreins in parasympathetic saliva must come from a non-granular pool, and are likely to be secreted through a constitutive vesicular route. During periods devoid of stimulation in anaesthetised rats, the kallikreins have been found to accumulate progressively in glandular lumina in parasympathetic-like proportions. As this transport of kallikrein into lumina occurs continuously in vivo, independently of any stimulation or any secretion of fluid, it must arise by constitutive vesicular secretion. During parasympathetic stimulation, the kallikreins are secreted into the saliva at a greater rate than in the resting state but their proportions remain the same and the means by which this increase occurs is open to debate. Constitutively secreted true tissue kallikrein (rK1) has been found to have a different molecular form from that in secretory granules. The submandibular glands also contribute to the kallikreins normally circulating in the blood. Serum levels of kallikrein increased equally during either parasympathetic or sympathetic stimulation and were independent of the amounts secreted into the saliva, so are likely to have arisen from constitutive secretion via the basal sides of the cells, morphological evidence for which has been found in the mouse (Penschow & Coghlan, 1993).

Animals↗
PubMed2002

Dynamic observations of their body constitution status in Zhuang students of Guangxi from 1985 to 2000.

OBJECTIVE: To study the rules of changes in body constitution of Zhuang students in Guangxi and factors influencing it. METHOD: Data on body constitution of Zhuang students aged seven to 22 in the year of 2000 were compared with those in 1985. RESULTS: The average height of Zhuang students increased by 3.80 cm and 2.45 cm for boys and girls in urban areas, respectively from 1985 to 2000 in Guangxi, and by 1.40 cm and 1.32 cm in rural areas, respectively. The average weight increased by 3.58 and 1.90 kg for boys and girls in urban areas, respectively, and by 0.65 kg and 0.02 kg in rural areas, respectively. The average chest circumference increased by 2.09 and 1.28 cm for boys and girls in urban areas, respectively, but in the rural areas, that for boys increased by 0.08 cm and for girls decreased by 0.01 cm. The average systolic blood pressure (BP) decreased by 4.33 mm Hg and 5.06 mm Hg (0.58 kPa and 0.67 kPa) for boys and girls in urban areas, respectively, and by 5.04 mm Hg and 7.03 mm Hg (0.67 kPa and 0.94 kPa) in rural areas, respectively. The average diastolic BP increased by 12.04 mm Hg and 10.84 mm Hg (1.60 kPa and 1.44 kPa) for boys and girls in urban areas, respectively, and by 8.72 mm Hg and 6.54 mm Hg (1.16 kPa and 0.87 kPa) in rural areas, respectively. The average vital capacity increased by 195.15 ml and 109.75 ml, and 23.54 ml and 13.44 ml for urban boys and girls, and rural boys and girls, respectively. The average record of 50 m x 8 run to and for decreased by 5.00 s and 8.79 s for urban boys and girls, respectively, and by 5.27 s and 7.21 s for rural boys and girls, respectively. The average record of 1 000 m run decreased by 19.85 s and 23.88 s for urban and rural boys, respectively, and that of 800 m run decreased by 23.19 s and 6.25 s for urban and rural girls, respectively. CONCLUSIONS: The results mentioned above suggested that provision of reasonable nutrition and active physical training for the Zhuang students are basic measures to improve their body constitution and promote their levels of growth and development.

Adolescent↗
PubMed2004

Molecular dynamics simulations of the human CAR ligand-binding domain: deciphering the molecular basis for constitutive activity.

The constitutive androstane receptor (CAR) belongs to the superfamily of nuclear-hormone receptors that function as ligand-activated transcription factors. CAR plays an essential role in the metabolism of xenobiotics and shows--in contrast to related receptors--constitutive activity. However, the molecular basis for the constitutive activity remains unclear. In the present study, homology models of the ligand binding domain (LBD) were generated based on the crystal structures of the related pregnane X (PXR) and the vitamin D receptor (VDR). The models were used to investigate the basal activity of CAR and the effect of coactivator binding. Molecular dynamics (MD) simulations of complexed and uncomplexed receptor revealed a hypothesis for the activation mechanism. The suggested mechanism is supported by experimental results from site-directed mutagenesis. The basal activity of CAR can be explained by specific van-der-Waals interactions between amino acids on the LBD and its C-terminal activation domain (AF-2). Docking studies with the GOLD program yielded the interaction modes of structurally diverse agonists, giving insight into mechanisms by which ligands enhance CAR activity.

Amino Acid Sequence↗
PubMed1996

High bone mass and altered relationships between bone mass, muscle strength, and body constitution in adolescent boys on a high level of physical activity.

We have recently demonstrated a general relationship between bone mass, muscle strength, and several body constitutional parameters in adolescent boys with a moderate exercise level. The present study was conducted to evaluate these previously described relationships in adolescent boys subjected to high physical activity and also to compare the bone mass of the same group with that of adolescents on a moderate level of physical activity. The reference group consisted of 24 boys, age 15.9 +/- 0.3 years, not training for more than 3 h per week. The ice hockey players consisted of 20 boys, age 15.9 +/- 0.3 years, from an ice hockey junior team training for about 10 h per week. The groups were matched according to age, pubertal stage, and weight. Areal bone mineral density (BMD) was measured in total body, head, humerus, spine, femur, and proximal femur using dual energy X-ray absorptiometry. BMD was significantly higher in the humerus (p < 0.01), femur (p < 0.05), and proximal femur (p < 0.05) in the high activity group. Furthermore, physical activity (h/week) was an independent predictor of humerus BMD (p < 0.01) and proximal femur BMD (p < 0.05), among all subjects investigated (n = 44). Isokinetic muscle strength of the quadriceps and hamstrings muscles was significantly higher in the high activity group (p < 0.05). In the reference group, there was a general strong independent relationship between BMD, muscle strength, and different body constitutional parameters. In the high activity group, muscle strength of the thigh independently predicted BMD of humerus and spine. Furthermore, in the same group, weight, BMI, and fat mass independently predicted only spine BMD. In conclusion, the higher BMD demonstrated in the ice hockey players seems to be site-specific and may well be associated with the type and magnitude of loading from predominantly ice hockey. High physical activity seems to weaken the relationship between BMD, muscle strength, and body constitution demonstrated in adolescent boys on a low or moderate level of physical activity.

Adolescent↗
PubMed2004

The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization.

Constitutive androstane receptor (CAR) induces xenobiotic, bilirubin, and thyroid hormone metabolism as a heterodimer with the retinoid X receptor (RXR). Unlike ligand-dependent nuclear receptors, CAR is constitutively active. Here, we report the heterodimeric structure of the CAR and RXR ligand binding domains (LBDs), which reveals an unusually large dimerization interface and a small CAR ligand binding pocket. Constitutive CAR activity appears to be mediated by the compact nature of the CAR LBD that displays several unique features including a shortened AF2 helix and helix H10, which are linked by a two-turn helix that normally adopts an extended loop in other receptors, and an extended helix H2 that stabilizes the canonical LBD fold by packing tightly against helix H3. These structural observations provide a molecular framework for understanding the atypical transcriptional activation properties of CAR.

Amino Acid Sequence↗
PubMed2003

Constitution and anthropometric parameters in indigenous population of Southern Altai Mountains.

Analysis of anthropometric parameters of 645 indigenous residents of Southern Altai Mountains belonging to two subethnic groups (165 Telengites and 480 Altai-Kizhi) revealed constitutional characteristics distinguishing these groups from each other and from Europeans. Differences in body length and weight, distribution by constitution types, sexual dimorphism, and AB0 blood groups were detected. The specific features of constitution together with environmental factors can determine predisposition of individuals belonging of these subethnic groups to some diseases.

ABO Blood-Group System↗