Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The first and rate-limiting step in the synthesis of all steroid hormones is the conversion of cholesterol to pregnenolone by the mitochondrial enzyme, P450scc. Tropic hormones such ACTH and gonadotropins induce steroidogenesis via cAMP by elaborating intracellular cAMP which stimulates P450scc activity in two distinct ways. Chronic stimulation (h to days) occurs through the induction of P450scc gene transcription leading to increased P450scc protein and consequent increased steroidogenic capacity. Acute regulation, over minutes, occurs through the phosphorylation of preexisting StAR and the rapid synthesis of new StAR protein. StAR, the steroidogenic acute regulatory protein, increases the flow of cholesterol into mitochondria, thus regulating substrate availability to whatever amount of P450scc is available. In the absence of StAR, up to 14% of maximal StAR-induced level of steroidogenesis persists as StAR-independent steroidogenesis. Congenital lipoid adrenal hyperplasia, an autosomal recessive disorder in which conversion of cholesterol to pregnenolone is severely impaired, results in female genitalia in 46,XY genetic males, variable onset of a severe salt-losing crisis in the first months of life, but normal feminization and cyclical vaginal bleeding in 46,XX females. Lipoid CAH was once thought to be due to P450scc mutations, but in fact homozygous P450scc mutations cannot exist in human beings as they would prohibit placental progesterone production, causing spontaneous abortion of the affected fetus. Lipoid CAH is caused by StAR mutations, which result in tropic hormone-induced intracellular accumulation of cholesterol in the adrenals and gonads. Our two-hit model, which considers the persistence of StAR-independent steroidogenesis and the differences in the fetal and postnatal ages at which the testis, adrenal zona glomerulosa, adrenal zona fasciculata and ovary are stimulated, predicts and explains all of the various clinical manifestations of lipoid CAH. Structure function studies of StAR show that the critical domains for biological activity reside in the protein's carboxy-terminus. When the N-terminal mitochondrial targeting sequences are deleted and the resulting N-62 StAR remains in the cytoplasm, it retains the ability to stimulate steroidogenesis both in intact cells or when added to isolated mitochondria in vitro. These observations suggest that StAR acts on the outer mitochondrial membrane to promote sterol translocation to P450scc, and that the importation of StAR into mitochondria terminates its action. Data from circular dichroism and Fourier-transform infrared spectroscopy show that the mutant StAR proteins in lipoid CAH are misfolded, suggesting disrupted interaction with another protein. Preliminary data suggest that StAR facilitates cholesterol desorption from membranes, stimulating transfer from the outer mitochondrial (donor) membrane to the inner mitochondrial (acceptor) membrane.
J Steroid Biochem Mol Biol
PMID:Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR. 1041 87

A large number of CD56(bright) natural killer (NK) cells, which comprise a very small fraction of peripheral blood lymphocytes, appear in the endometrium during the late secretory phase and early pregnancy. These cells are thought to immunologically maintain or inhibit pregnancy. However, the details regarding their contribution to the immuno-elimination systems of embryonic cells or decidual stromal cells remain unclear. Recently, leukocyte function-associated antigen-1 (LFA-1) was shown to play a critical role in the regulation of NK cytolysis in peripheral blood lymphocytes. We speculated that LFA-1 on the decidual CD56(bright) NK may be involved in the regulation of pregnancy. The expression of LFA-1 on the decidual CD56(bright) NK cells was analysed using flow cytometry with fluorescent monoclonal antibodies; CD56 (NKH1), CD16 (Fcg-R3) and CD11a (LFA-1 alpha-chain). In comparison with non-pregnant endometrium during the late secretory phase, the subpopulation of CD56(bright)CD16(-) cells in decidual lymphocytes was significantly increased during normal pregnancy, but was less than that in early pregnancy loss (P < 0.05). Furthermore, the number of CD56(bright) NK cells expressing LFA-1 was significantly higher in early pregnancy loss, and the late secretory phase, than during normal pregnancy (P < 0.05). Our results indicate that up-regulation of LFA-1 on CD56(bright) NK cells is related to spontaneous abortion or the onset of menstruation.
Mol Hum Reprod 1999 Nov
PMID:Leukocyte function-associated antigen-1 expression on decidual natural killer cells in patients with early pregnancy loss. 1054 72

Brucella abortus is a facultative intracellular pathogen that causes abortion and infertility in domestic animals and a severe debilitating febrile illness in humans. The mechanisms that this highly successful intracellular pathogen uses to adapt to, and survive within, the harsh intracellular environment of the host macrophage are presently unknown. Maintenance of the stationary phase growth state has been proposed to be critical for the virulence of several mammalian pathogens, but analysis of this relationship for the brucellae has not been undertaken. In order to evaluate this relationship, we examined the in vitro and in vivo characteristics of an isogenic hfq mutant constructed from virulent Brucella abortus 2308. In Escherichia coli, the hfq gene product is an RNA-binding protein that participates in the regulation of stationary phase stress resistance, at least partly by enhancing translation of the stationary phase-specific sigma factor RpoS. As expected, the Brucella abortus hfq mutant, designated Hfq3, showed increased sensitivity to H2O2, and decreased survival under acidic conditions (pH 4.0), during stationary phase growth compared with 2308. Hfq3 was also less able to withstand prolonged starvation than 2308. The Brucella abortus hfq mutant, unlike its parental strain 2308, fails to replicate in cultured murine macrophages, and is rapidly cleared from the spleens and livers of experimentally infected BALB/c mice. These findings suggest that the Brucella abortus hfq gene product makes an essential contribution to pathogenesis in mice, probably by allowing the brucellae to adapt appropriately to the harsh environmental conditions encountered within the host macrophage.
Mol Microbiol 1999 Nov
PMID:The Brucella abortus host factor I (HF-I) protein contributes to stress resistance during stationary phase and is a major determinant of virulence in mice. 1056 9

Preimplantation genetic diagnosis (PGD) was performed in two couples to avoid chromosomally unbalanced progeny in a family in which a brother and a sister carry an identical maternally inherited balanced translocation t(3;11)(q27.3;q24.3). Embryos were biopsied 3 days after fertilization and blastomeres were analysed by fluorescent in-situ hybridization (FISH). Embryos were classified as unbalanced or normal/balanced. In the first case, the male carrier and his wife underwent one IVF/PGD treatment cycle. In all, 18 embryos were analysed. Of those, 15 revealed an unbalanced karyotype. For one embryo, results were not conclusive, from one embryo results were contradictory and one embryo was classified as normal/balanced and subsequently transferred. A singleton pregnancy was achieved. The PGD analysis was confirmed at 16 weeks gestation by amniocentesis. At term, a healthy girl with a balanced karyotype was born. Pregnancy and delivery were without complications. In the second case, the female carrier and her husband underwent two IVF/PGD treatment cycles. During the first cycle, three embryos were analysed. One embryo revealed an unbalanced karyotype and two embryos were designated a normal/balanced karyotype and transferred but no pregnancy was achieved. During the second PGD cycle three embryos were analysed. Of those, none appeared suitable for transfer. The couple decided not to undergo further treatment. Our results indicate that for individuals carrying a reciprocal translocation PGD is a feasible approach to obtain embryos with a normal chromosome balance and to avoid both spontaneous and induced abortion.
Mol Hum Reprod 2000 Mar
PMID:Preimplantation genetic diagnosis of a reciprocal translocation t(3;11)(q27.3;q24.3) in siblings. 1069 65

The aetiology of recurrent miscarriage (at least three consecutive miscarriages) usually remains unsolved. The vascular endothelial growth factor (VEGF) family of proteins, together with their receptors and the Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) receptors, are crucial for embryonic development. Therefore, we used immunohistochemistry to analyse the expression of VEGF, the VEGF receptors (VEGFR)-1, -2, and -3, and the Tie-1 and Tie-2 receptors in placental and decidual tissue of women with a history of recurrent miscarriage and missed abortion (MA; n = 12) or blighted ovum (BO; n = 6), and from normal early terminated pregnancies (n = 12). Compared with controls, the MA and BO groups showed: (i) diminished placental trophoblastic VEGF immunoreactivity; (ii) weaker VEGFR-1 and -2 immunoreactivity in decidual vascular endothelium; (iii) reduced placental trophoblastic Tie-1 receptor immunoreactivity; and (iv) reduced decidual vascular endothelial Tie-1 and -2 receptor immunoreactivity. The absence of VEGFR-3 immunoreactivity in decidual vascular endothelium was also noted in all study groups. Interestingly, placental villi from the BO group presented blood vessel-like structures negative for von Willebrand factor, but positive for VEGF, VEGFR-1, -2, -3, Tie-1 and Tie-2 receptor. We conclude that the expression of these antigens may be altered in recurrent miscarriages.
Mol Hum Reprod 2000 Mar
PMID:VEGF, its receptors and the tie receptors in recurrent miscarriage. 1069 77

V(D)J recombination, accountable for the diversity of T cell receptor- and immunoglobulin-encoding genes, is initiated by a lymphoid-specific DNA double-strand break. The general DNA repair machinery is responsible for the resolution of this break. Any defect in one of the known components of the DNA repair/V(D)J recombination machinery (Ku70, Ku80, DNA-PKcs, XRCC4 and DNA ligase IV) leads to abortion of the V(D)J rearrangement process, early block in both T and B cell maturation, and ultimately to severe combined immune deficiency (SCID) in several animal models. A human SCID condition is also characterized by an absence of mature T and B lymphocytes, and is associated with an increase in sensitivity to DNA-damaging agents (RS-SCID). None of the above-mentioned genes are defective in these patients, arguing for the likelihood of the existence of yet another unknown component of the V(D)J recombination/DNA repair apparatus. Athabascan-speaking (SCIDA) Navajo and Apache Native Americans have a very high incidence of T(-)B(-)SCID. The SCIDA locus is highly linked with markers on chromosome 10p, although the exact molecular defect has not been recognized in these patients. We show here that cells with the SCIDA defect are impaired in the DNA repair phase of V(D)J recombination similarly to RS-SCID, precisely an absence of V(D)J coding joint formation. Moreover, genotyping analysis in several RS-SCID families corroborates a linkage of the RS-SCID locus to the SCIDA region on chromosome 10p. These results demonstrate the presence of a new essential DNA repair/V(D)J recombination gene in this region, the mutation of which causes RS-SCID in humans.
Hum Mol Genet 2000 Mar 01
PMID:A new gene involved in DNA double-strand break repair and V(D)J recombination is located on human chromosome 10p. 1069 81

Chromosomal analysis of pre-implantation embryos was carried out in patients with a poor prognosis of full term pregnancy, which underwent induction of multiple follicular growth. In all, 1034 embryos generated from 191 stimulated cycles were screened for nine chromosome aneuploidy by using the multicolour fluorescence in situ hybridisation technique. Thirty-five percent of the diagnosed embryos were chromosomally normal, whereas the remaining presented with numerical abnormalities, which made them not suitable for transfer. The results obtained confirmed that the incidence of abnormalities is mostly dependent on age; however, monosomy and trisomy are more frequent in poor responders. Accordingly, the pregnancy rate per started cycle was significantly higher in women with a normal response to gonadotropic stimulation (33% vs. 8%, P<0. 001). These findings indicate that poor responder patients are physiologically exposed not only to reduced chances of implantation, but also to an increased risk of spontaneous abortion and trisomic pregnancies.
Mol Cell Endocrinol 2000 Mar 30
PMID:Gonadal activity and chromosomal constitution of in vitro generated embryos. 1077 99

To study the possible role of the superoxide radical and its scavenging system in the decidua of early pregnancy, superoxide dismutase (SOD) values and concentrations of lipid peroxide and prostaglandin F(2alpha) (PGF(2alpha)) were analysed in the decidua obtained from normal pregnancy and failed pregnancy. Failed pregnancy was divided into two groups; spontaneous abortion with or without vaginal bleeding. In the spontaneous abortion with vaginal bleeding, total SOD activities, Cu,Zn-SOD activities and Cu,Zn-SOD mRNA values in the decidua were significantly lower, and concentrations of lipid peroxide and PGF(2alpha) were significantly higher, than those in the normal pregnancy and the spontaneous abortion without vaginal bleeding. In contrast, activities and mRNA values of Mn-SOD were significantly higher in the spontaneous abortion with vaginal bleeding than the other two groups. There was no significant difference in all of these parameters between the normal pregnancy and the spontaneous abortion without vaginal bleeding. In conclusion, the decrease in Cu,Zn-SOD expression and the increase in lipid peroxide in the decidua could be involved in the termination of spontaneous abortion, mediated through the increase in PGF(2alpha) synthesis. In other words, Cu,Zn-SOD may contribute to the maintenance of pregnancy by preventing the accumulation of superoxide radicals that cause PGF(2alpha) synthesis.
Mol Hum Reprod 2000 Jul
PMID:Decreased superoxide dismutase expression and increased concentrations of lipid peroxide and prostaglandin F(2alpha) in the decidua of failed pregnancy. 1087 52

DnaB helicase is a ring-shaped hexamer that unwinds DNA at a replication fork. To understand how this protein interacts with DNA during unwinding, DnaB from Thermus aquaticus was incubated with chemically modified forked-duplex DNA substrates and the unwinding rates were measured. Unwinding was inhibited by modifications made to the 5'-tail, but not the 3'-tail, suggesting that the helicase interacts with the 5'-tail but not the 3'-tail during unwinding. Using oligonucleotides of mixed polarity, it was confirmed that DnaB translocates in the 5' to 3' direction as it unwinds DNA. A substrate was synthesized that contained two duplexes in tandem. Experiments involving various modifications of this tandem duplex demonstrated that when the 3'-tail is short, two stands of DNA pass through the central channel of DnaB with no resultant unwinding. Thus, the role of the 3'-tail in stimulating unwinding has been elucidated. The 3'-tail does not bind to DnaB during unwinding, but sterically determines whether one or two DNA strands pass through the central channel of DnaB. Furthermore, a new substrate for DnaB locomotion has been discovered. DnaB may actively translocate in the 5' to 3' direction along single-stranded DNA, even when a complementary strand is also present within the protein's central channel. This new mode of action may regulate DnaB activity by inhibiting unwinding at regions of DNA that are not forked. Furthermore, this new function for DnaB may coordinate abortion of leading and lagging strand replication if a nick is encountered on the leading strand.
J Mol Biol 2000 Aug 11
PMID:The 3'-tail of a forked-duplex sterically determines whether one or two DNA strands pass through the central channel of a replication-fork helicase. 1092 10

Brucella melitensis 16M is a Gram-negative alpha2-proteobacterium responsible for abortion in goats and for Malta fever in humans. This facultative intracellular pathogen invades into and survives within both professional and non-professional phagocytes. Signature-tagged mutagenesis (STM) was used to identify genes required for the in vivo pathogenesis of Brucella. A library of transposon mutants was screened in a murine infection model. Out of 672 mutants screened, 20 were not recovered after a 5 day passage in BALB/c mice. The attenuation of 18 mutants was confirmed using an in vivo competition assay against the wild-type strain. The 18 mutants were characterized further for their ability to replicate in murine macrophages and in HeLa cells. The sequences disrupted by the transposon in the mutants have homology to genes coding for proteins of different functional classes: transport, amino acid and DNA metabolism, transcriptional regulation, peptidoglycan synthesis, a chaperone-like protein and proteins of unknown function. The mutants selected in this study provide new insights into the molecular basis of Brucella virulence.
Mol Microbiol 2000 Nov
PMID:Identification and characterization of in vivo attenuated mutants of Brucella melitensis. 1106 78


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