calcimycin and Down-Syndrome

The Down syndrome critical region 1 (DSCR1) gene (also known as MCIP1, Adapt78) encodes a regulatory protein that binds to calcineurin catalytic A subunit and acts as a regulator of the calcineurin-mediated signaling pathway. We show in this study that DSCR1 is greatly induced in endothelial cells in response to VEGF, TNF-alpha, and A23187 treatment, and that this up-regulation is inhibited by inhibitors of the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway as well as by PKC inhibition and a Ca(2+) chelator. We hypothesized that the up-regulation of DSCR1 gene expression in endothelial cells could act as an endogenous feedback inhibitor for angiogenesis by regulating the calcineurin-NFAT signaling pathway. Our transient transfection analyses confirm that the overexpression of DSCR1 abrogates the up-regulation of reporter gene expression driven by both the cyclooxygenase 2 and DSCR1 promoters in response to stimulators. Our results indicate that DSCR1 up-regulation may represent a potential molecular mechanism underlying the regulation of angiogenic genes activated by the calcineurin-NFAT signaling pathway in endothelial cells.

Topics: Calcimycin; Calcineurin; Calcineurin Inhibitors; Cells, Cultured; Cyclooxygenase 2; DNA-Binding Proteins; Down Syndrome; Endothelial Cells; Endothelium, Vascular; Enzyme Inhibitors; Feedback, Physiological; Gene Expression Regulation; Genes, Reporter; Humans; Intracellular Signaling Peptides and Proteins; Ionophores; Isoenzymes; Membrane Proteins; Muscle Proteins; Neovascularization, Physiologic; NFATC Transcription Factors; Nuclear Proteins; Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases; Protein Isoforms; RNA, Messenger; Signal Transduction; Transcription Factors; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

To describe a successful pregnancy and delivery from frozen-thawed embryos after intracytoplasmic sperm injection (ICSI) and assisted oocyte activation in a globozoospermic patient with mosaic Down syndrome.. Controlled clinical study.. IVF Laboratory, PL Infertility Clinic, Seoul, Korea.. A couple with infertility resulting from globozoospermia with mosaic Down syndrome: 47,XY,+21[7]/46,XY[33].. Semen analysis, karyotyping, ICSI, assisted oocyte activation, assisted hatching, and frozen-thawed ET.. Fertilization rate, implantation, pregnancy, and delivery.. Thirty-eight oocytes were aspirated, and round-headed spermatozoa were injected into 35 oocytes in metaphase II. Assisted oocyte activation with calcium ionophore A23187 after ICSI resulted in a high fertilization rate (21 of 35, 60%; 2 pronuclei in 18 of 21; 3 pronuclei in 3 of 21) and good embryo development. At 3 days after ICSI, 5 embryos of good quality were surgically transferred to the endometrium after assisted hatching, but no pregnancy occurred. After 2 months, the surgical transfer of 4 frozen-thawed embryos after assisted hatching led to an ongoing pregnancy. A female infant weighing 3,000 g was delivered at 38 weeks of gestation by cesarean section.. We report the first successful pregnancy and delivery from frozen-thawed embryos after ICSI and assisted oocyte activation in a globozoospermic patient with mosaic Down syndrome.

Topics: Adult; Calcimycin; Cesarean Section; Cryopreservation; Down Syndrome; Embryo Implantation; Embryo Transfer; Embryo, Mammalian; Female; Humans; Infertility, Male; Ionophores; Male; Mosaicism; Oocytes; Pregnancy; Pregnancy Outcome; Sperm Head; Sperm Injections, Intracytoplasmic; Spermatozoa

The proliferative response of purified T cells to anti-CD2 monoclonal antibodies (T112 plus T113) was found to be markedly reduced in 12 subjects with Down's syndrome (DS). The addition of phorbol ester PMA, which activates Ca2+/phospholipid-dependent enzyme protein kinase C, or calcium ionophore A23187, which increases intracytosolic free Ca2+ concentration, enhanced, but did not normalize, the defective anti-CD2-mediated T-cell mitogenesis. In contrast, the proliferation of resting lymphocytes from trisomic patients was comparable to that of the control cells when PMA and A23187 were used as co-blastogenic reagents. Because PMA and A23187 together bypass the early activation pathways and promote T-cell growth through the direct induction of membrane interleukin 2 (IL-2) receptor expression and IL-2 synthesis and secretion, it could reasonably be hypothesized that the faulty DS T-cell activation induced by antigen or mitogen is due to a deranged transmembrane signal transduction, rather than a defect in the later intracellular events.

Topics: Adolescent; Adult; Antigens, Differentiation, T-Lymphocyte; Calcimycin; CD2 Antigens; Child; Down Syndrome; Humans; Lymphocyte Activation; Middle Aged; Receptors, Immunologic; T-Lymphocytes; Tetradecanoylphorbol Acetate