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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adipose tissue and muscle constitute the larger proportion of body mass, and therefore aromatization in these tissues is the major source of circulating estrogens in postmenopausal women. Although plasma estrogen concentrations are very low, levels in breast cancers from postmenopausal patients are reported to be 10-fold higher than in plasma and normal tissue. Whereas studies on aromatase activity in the tumor suggest that estrogen may be produced locally, the significance of this contribution has been questioned. Using immunocytochemistry (ICC) to an anti-aromatase antibody, a relatively strong immunoreaction was detected in tumor epithelial cells as well as in the terminal ductal lobular units (TDLUs) of the normal breast. Aromatase expression was detected in the cytoplasm of tumor epithelial cells and the surrounding stromal cells of over 50% of tumors in a series of 19 breast cancers. In situ hybridization (ISH) to aromatase mRNA confirmed the immunocytochemical result that the epithelial cells are the primary site of estrogen synthesis in the breast and breast cancers. In the 10 tumors which showed immunoreaction to aromatase, the average aromatase activity measured in cryosections was 286.5 +/- 18.6 fmol estrogen/mg protein/h (SE), whereas in nine tumors with weak aromatase immunoreaction, the enzyme activity was 154.7 +/- 19.3 fmol estrogen/mg protein/h (P < 0.05) (SE). The functional significance of tumor aromatase and locally produced estrogens on the growth of tumors was suggested by the correlation between aromatase activity and proliferating cell nuclear antigen (PCNA), a marker of cell proliferation (P < 0.005). Although intratumoral aromatase activity did not correlate with steroid receptors significantly, there was a trend for estrogen receptor (ER)-positive tumors to express aromatase. In addition, proliferation ([3H]-thymidine incorporation into DNA) during histoculture, was increased by both estradiol and testosterone in tumors with high aromatase activity. Our results suggest that some tumors synthesize sufficient estrogen to stimulate their proliferation. It may thus be important to inhibit tumor aromatase as well as to reduce circulating levels of estrogen for effective breast cancer treatment.
J Steroid Biochem Mol Biol 1997 Apr
PMID:Aromatase in the normal breast and breast cancer. 936 2

Abnormal angiogenesis underlies many pathological conditions and is critical for the growth and maintenance of various types of tumors, including hormone-dependent cancers. Since estrogens are potent carcinogens in humans and rodents, and are involved in regulating angiogenesis, this study was designed to examine the effect of estrogen on the behavior of an established bovine capillary endothelial cell line, a simple and physiologically relevant model of the capillary wall. The results demonstrate that 17beta-estradiol (E2), at different conditions, exerts both stimulatory and inhibitory effects on endothelial cell adhesion, proliferation and tube formation in vitro. Utilizing a cellular attachment assay, chronic exposure to nanomolar concentrations of E2 (i.e. 1 and 10 nM) increased endothelial cell adhesion significantly compared to vehicle treated controls. Cellular adhesion was inhibited by micromolar concentrations of E2. Cell count, PCNA immunohistochemistry and Western blot analysis demonstrated enhanced cell proliferation at low E2 concentration in estrogen-deplete medium. Inhibition of cellular proliferation was observed in both estrogen-replete and deplete medium at higher E2 concentrations (i.e. 1 and 10 microM). Furthermore, in vitro tube formation increased up to 3.0 fold in the presence of 10 nM and higher E2 concentrations. The present observations indicate that in vitro regulation of capillary endothelial cell adhesion, proliferation and capillary tube formation by estrogen, are dose dependent.
Mol Cell Biochem 1997 Dec
PMID:Biphasic estrogen response on bovine adrenal medulla capillary endothelial cell adhesion, proliferation and tube formation. 945 Jun 50

The function of proliferating cell nuclear antigen (PCNA) in DNA replication and repair is to form a sliding clamp with replication factor C (RF-C) tethering DNA polymerase delta or epsilon to DNA. In addition, PCNA has been found to interact directly with various proteins involved in cell cycle regulation. The crystal structure of yeast PCNA shows that the protein forms a homotrimeric ring lining a hole through which double-stranded DNA can thread, thus forming a moving platform for DNA synthesis. Human and yeast PCNA are highly conserved at a structural and functional level. We determined the solution structure of functionally active human PCNA by small-angle neutron scattering. Our measurements strongly support a trimeric ring-like structure of functionally active PCNA in solution, and the data are in good agreement with model calculations based on the crystal structure from yeast PCNA. The human PCNA used in the small-angle neutron scattering experiments was active before and after the measurements in a RF-C independent and a RF-C dependent assay suggesting that the trimeric structure is the in vivo functional form.
J Mol Biol 1998 Jan 09
PMID:The solution structure of functionally active human proliferating cell nuclear antigen determined by small-angle neutron scattering. 945 44

In a total of 41 endometrial tissue samples, the relationship between telomerase activity and proliferating cell nuclear antigen (PCNA) labelling index was studied. In samples of endometrium from the proliferative phase of the menstrual cycle, telomerase activity was found in 15 out of 17 cases (88%). Two samples from the early proliferative phase showed negative telomerase activity and a low PCNA labelling index. However, three out of 16 samples of early secretory phase endometrium showed telomerase activity and a PCNA labelling index. In mid- to late secretory phase endometrium, in menopausal endometrium and in decidualized endometrium induced by progesterone neither telomerase activity nor PCNA labelling was found. These results suggest that telomerase activity of the endometrium may be correlated with the proliferative potential of the epithelial cells and that its activity may be regulated by oestrogen.
Mol Hum Reprod 1998 Feb
PMID:Telomerase activity in the human endometrium throughout the menstrual cycle. 954 76

Twenty-eight site-directed mutations were introduced into the fission yeast gene (pcn1+) that encodes proliferating cell nuclear antigen (PCNA) and their in vivo effects analyzed in a strain with a null pcn1 background. Mutants defective in enhancing processivity of DNA polymerase delta have previously been identified. In this study, we assessed all of the mutants for their sensitivities to temperature, hydroxyurea, UV irradiation and methyl methanesulfonate (MMS), and specific mutants were also tested for sensitivity to gamma irradiation. One cold-sensitive allele, pcn1-3, was characterized in detail. This mutant had a recessive cold-sensitive cdc phenotype and showed sensitivity to hydroxyurea, UV, and gamma irradiation. At the non-permissive temperature pcn1-3 protein was able to form homotrimers in solution and showed increased stimulation of both synthetic activity and processivity of DNA polymerase delta relative to the wild-type Pcn1+ protein. Epistasis analyses indicated that pcn1-3 is defective in the repair pathway involving rad2+ but not defective in the classical nucleotide excision repair pathway involving rad13+. Furthermore, pcn1-3 is either synthetically or conditionally lethal in null checkpoint rad backgrounds and displays a mitotic catastrophe phenotype in these backgrounds. A model for how pcn1-3 defects may affect DNA repair and replication is presented.
Mol Gen Genet 1998 Mar
PMID:Mutant PCNA alleles are associated with cdc phenotypes and sensitivity to DNA damage in fission yeast. 956 36

In a two-hybrid screen for proteins that interact with human PCNA, we identified and cloned a human protein (hCdc18) homologous to yeast CDC6/Cdc18 and human Orc1. Unlike yeast, in which the rapid and total destruction of CDC6/Cdc18 protein in S phase is a central feature of DNA replication, the total level of the human protein is unchanged throughout the cell cycle. Epitope-tagged protein is nuclear in G1 and cytoplasmic in S-phase cells, suggesting that DNA replication may be regulated by either the translocation of this protein between the nucleus and the cytoplasm or the selective degradation of the protein in the nucleus. Mutation of the only nuclear localization signal of this protein does not alter its nuclear localization, implying that the protein is translocated to the nucleus through its association with other nuclear proteins. Rapid elimination of the nuclear pool of this protein after the onset of DNA replication and its association with human Orc1 protein and cyclin-cdks supports its identification as human CDC6/Cdc18 protein.
Mol Cell Biol 1998 May
PMID:Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase. 956 95

The quantitative distribution pattern of Ki-67 protein and proliferating cell nuclear antigen (PCNA) immunoreactivity was studied in human testis biopsies. In normal seminiferous epithelium Ki-67 is expressed in nuclei of spermatogonia, while PCNA additionally occurs in nuclei of primary spermatocytes. The staining pattern of spermatogonia is as follows (Ki-67-positive/PCNA-positive): 26.6 +/- 12.4%/46.3 +/- 9.5%. No stage-dependent differences were found. Biopsies with mixed atrophy (score < or =7) showed a significant (P < 0.05) decrease of immunopositive spermatogonia to 19.9 +/- 3.0%/31.4 +/- 5.7% (score 1) with minimal variation between different samples (score 7 to 1). Associated with defined histological defects such as hypospermatogenesis (hyp), spermatogenic arrest at the level of spermatids (sda), spermatocytes (sca) or spermatogonia (sga), however, there was a significant (P < 0.05) decrease of Ki-67 staining in tubules showing hyp (28.6 +/- 8.8%), sda (25.6 +/- 9.3%), sca (23.7 +/- 9.3%) and sga (16.2 +/- 6.0%) and of PCNA staining in sca (32.2 +/- 11.8%) and sga (20.0 +/- 9.5%), respectively. The decrease of immunoreactive spermatogonia did not correspond to elevation of follicle stimulating hormone (FSH). These data demonstrate that the low spermatogenic efficiency in infertile men is not only due to postmeiotic events, but also to a decrease in the meiotic activity of spermatogonia, and is not related to serum FSH.
Mol Hum Reprod 1998 Mar
PMID:The proliferation of spermatogonia in normal and pathological human seminiferous epithelium: an immunohistochemical study using monoclonal antibodies against Ki-67 protein and proliferating cell nuclear antigen. 957 Feb 68

Observations made with Escherichia coli have suggested that a lag between replication and methylation regulates initiation of replication. To address the question of whether a similar mechanism operates in mammalian cells, we have determined the temporal relationship between initiation of replication and methylation in mammalian cells both at a comprehensive level and at specific sites. First, newly synthesized DNA containing origins of replication was isolated from primate-transformed and primary cell lines (HeLa cells, primary human fibroblasts, African green monkey kidney fibroblasts [CV-1], and primary African green monkey kidney cells) by the nascent-strand extrusion method followed by sucrose gradient sedimentation. By a modified nearest-neighbor analysis, the levels of cytosine methylation residing in all four possible dinucleotide sequences of both nascent and genomic DNAs were determined. The levels of cytosine methylation observed in the nascent and genomic DNAs were equivalent, suggesting that DNA replication and methylation are concomitant events. Okazaki fragments were also demonstrated to be methylated, suggesting that the rapid kinetics of methylation is a feature of both the leading and the lagging strands of nascent DNA. However, in contrast to previous observations, neither nascent nor genomic DNA contained detectable levels of methylated cytosines at dinucleotide contexts other than CpG (i.e., CpA, CpC, and CpT are not methylated). The nearest-neighbor analysis also shows that cancer cell lines are hypermethylated in both nascent and genomic DNAs relative to the primary cell lines. The extent of methylation in nascent and genomic DNAs at specific sites was determined as well by bisulfite mapping of CpG sites at the lamin B2, c-myc, and beta-globin origins of replication. The methylation patterns of genomic and nascent clones are the same, confirming the hypothesis that methylation occurs concurrently with replication. Interestingly, the c-myc origin was found to be unmethylated in all clones tested. These results show that, like genes, different origins of replication exhibit different patterns of methylation. In summary, our results demonstrate tight coordination of DNA methylation and replication, which is consistent with recent observations showing that DNA methyltransferase is associated with proliferating cell nuclear antigen in the replication fork.
Mol Cell Biol 1998 Jun
PMID:Concurrent replication and methylation at mammalian origins of replication. 958 87

The gene coding for proliferating cell nuclear antigen (PCNA) was identified in Dunaliella tertiolecta (Chlorophyceae) and Isochrysis galbana (Prymnesiophyceae). Southern blot hybridization using a PstI fragment of rat PCNA gene (pCR-1) as a probe showed that there is apparently a single copy of this gene per haploid genome in both species. On the Northern blot pCR-1 probed a single messenger RNA for each species of a molecular size close to rat PCNA mRNA (1.1 kilobases [kb]). Polymerase chain reaction (PCR) with a set of degenerated primers produced a fragment of about 610 base pairs [bp] from genomic DNA of both species; the PCR products appeared close in size to the amplified from rat PCNA and hybridized to the pCR-1 probe. Further analysis with reverse transcription-PCR (RT-PCR), cloning, and sequencing revealed a complementary DNA of a similar size (616 and 576 bp) that possesses an open reading frame encoding 205 and 192 amino acids, respectively, for Dun (D. tertiolecta) and Iso (I. galbana). Surprisingly, the polypeptides deduced from the two cDNA shared no higher homology to each other (71%) than to animals such as Xenopus (Dun 72%; Iso 73%), rat (Dun 73%; Iso 74%), and human (Dun 73%; Iso 74%), and to higher plants such as soybean (Dun 78%; Iso 72%), Zea mays (Dun 77%; Iso 73%), and rice (Dunn 77%; Iso 72%), although D. tertiolecta has a higher homology (77%) to the Prasinophyceae alga Tetraselmis chiu than does I. galbana (71%). The homology to PCNA in budding and fision yeasts (63% and 53%, respectively) is also lower than to animals and higher plants. It is thus suggested that with regard to PCNA genes, the three algae are as different from each other as they are from higher plants and animals. In a partially synchronized exponential culture of D. tertiolecta grown with a photocycle of 12 h light and 12 h dark, the abundance of the transcript appeared to be low at hours 3 and 9 (hour 0 = the onset of light period), and increased about 2- to 3-fold at hours 15 and 21 (i.e., during the dark period). Western blotting and immunofluorescence analysis on concurrent diel samples showed an over 2-fold increase in PCNA protein abundance (in proportion to total cellular protein) and the percentage of cells labeled by PCNA antibody. A similar trend was found for I. galbana grown under the same conditions. The results suggest that the gene transcription was in pace with PCNA synthesis, which was lower in the light period when G1 phase was dominant and higher in the dark period when S (and probably G2 and early M) phase was dominant, and that the expression of this gene may be regulated at the transcriptional level in these two algae.
Mol Mar Biol Biotechnol 1998 Mar
PMID:Identification and preliminary characterization of PCNA gene in the marine phytoplankton Dunaliella tertiolecta and Isochrysis galbana. 959 79

Insulin-like growth factor I (IGF-I)/insulin induced cytosolic p42/p44 mitogen-activated protein kinase (MAPK) activation in a time-dependent manner in fetal brown adipocytes, reaching a maximum at 5 min. Concurrently, nuclear p42/p44 MAPKs were also activated by IGF-I and insulin. This cytosolic and nuclear MAPK activation was totally prevented by pretreatment with the MAPK kinase (MEK1) inhibitor, PD98059. These results indicate that MEK mediates the IGF-I/insulin-induced p42/ p44 MAPK activation. IGF-I and insulin also increased the number of cells in the S + G2/M phases of the cell cycle, PCNA levels, and DNA synthesis at 24 h. This IGF-I/insulin-induced proliferation was completely blunted by the presence of MEK1 inhibitor. In contrast, inhibition of MEK1 potentiated the IGF-I-induced uncoupling protein (UCP-1) and the insulin-induced fatty acid synthase mRNAs expression after short and long-term treatments. Moreover, transient expression of a transfected active MEK construct (R4F) decreased IGF-I-induced UCP-1 and insulin-induced fatty acid synthase mRNA expression. These results demonstrate that p42/p44 MAPKs are essential intermediates for the IGF-I/insulin-induced mitogenesis, but may have a negative role in the regulation of adipocytic and thermogenic differentiation in brown adipocytes.
Mol Endocrinol 1998 Jun
PMID:p42/p44 mitogen-activated protein kinases activation is required for the insulin-like growth factor-I/insulin induced proliferation, but inhibits differentiation, in rat fetal brown adipocytes. 962 58


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