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T Fredrickson

Publications and source records attributed to T Fredrickson.

18 recordsLinked to original sources
PubMed2001

Molecular cloning and characterization of profilin-3: a novel cytoskeleton-associated gene expressed in rat kidney and testes.

Profilin is a small actin-binding protein that is involved in diverse functions such as maintaining cell structure integrity, cell mobility, tumor cell metastasis, as well as growth factor signal transduction. In this paper, we describe the molecular cloning and characterization of a novel form of profilin, termed profilin-3, from rat kidney using a PCR-based procedure for isolating tissue-specific genes. The profilin-3 cDNA encoded 137 amino acids, and it shared extensive homology to profilin-1 and profilin-2 from mice and humans. More strikingly, the expression of profilin-3 was highly selective, and its mRNA was only found in the kidney and to a much lesser extent in the testis. The size of the mRNA for profilin-3 in the testis was 1.2 kb, while in kidney it was approximately 4.4-5 kb, suggesting the presence of tissue-specific transcription from different promoters. In addition, we also found that the expression of profilin-3 mRNA was significantly elevated in two types of renal diseases: diabetic nephropathy (db/db mice) and polycystic kidney diseases (cpk mice). Similar to profilin-1 and profilin-2, profilin-3 was localized in the cytoplasmic domain. Furthermore, it was capable of interacting with actin and poly-L-proline in an in vitro assay as well as in transfected cells. These results strongly suggest that, contrary to the ubiquitous presence of profilin-1 and profilin-2, there is a tissue-specific form of these cytoskeleton-regulatory proteins and that the kidney/testes-specific profilin-3 may play a unique role in renal and/or reproductive functions.

3T3 Cells↗
PubMed2000

Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor.

Histone acetylation alters chromatin state by modifying lysines on histone and plays an important role in modulating gene transcription. A dynamic balance of histone acetylation/deacetylation is maintained by histone acetyltransferases and histone deacetylases. Emerging evidence suggests that a family of histone deacetylases may exist to regulate diverse cellular functions, including chromatin structure, gene expression, cell cycle progression, and oncogenesis. We describe here a novel human histone deacetylase, named HDAC8, cloned from human kidney. HDAC8 encodes 377 amino acid residues and shares extensive homology to several known HDACs, in particular a histone deacetylase from Arabidopsis thaliana. Northern blot analyses revealed that HDAC8 expression pattern for HDAC8 is distinct from that for HDAC1 and HDAC3, and expression of HDAC8 mRNA occurs in multiple organs including heart, lung, kidney, and pancreas. HDAC8 mRNA was also observed in several cell lines derived from cancerous tissues. When expressed in HEK293 cells, HDAC8 exhibited deacetylase activity toward acetylated histone, indicating that this protein is a bona fide histone deacetylase. Its histone deacetylase activity was inhibited by trichostatin and other known histone deacetylase inhibitors. Furthermore, active recombinant HDAC8 was expressed and purified from Escherichia coli. When ectopically expressed in cells, HDAC8 was found to be localized to the nucleus. Co-transfection experiments demonstrated that expression of HDAC8 repressed a viral SV40 early promoter activity. These results indicate that HDAC8 is a novel member of the histone deacetylase family, which may play a role in the development of a broad range of tissues and potentially in the etiology of cancer.

3T3 Cells↗
PubMed2000

Identification of a novel kidney-specific gene downregulated in acute ischemic renal failure.

To gain further insights into the molecular mechanisms involved in acute renal failure, we have isolated a new gene from rat and human, named KSP32 (kidney-specific protein with a molecular mass of 32 kDa). KSP32 encodes a novel gene that shows little homology to other mammalian proteins. It, however, shares extensive homology with several proteins found in the nematode Caenorhabditis elegans and plants. The expression of KSP32 mRNA is highly restricted to kidney. In situ hybidization analysis revealed that the expression of KSP32 mRNA was prominent in the boundary of kidney cortex and outer medulla, exhibiting a raylike formation extending from the medulla into the cortex. Finally, KSP32 mRNA was dramatically downregulated in rat following induction of acute ischemic renal failure. Rapid loss of KSP32 mRNA expression was observed beginning at approximately 5 h following renal injury and mRNA levels remained depressed for at least 96 h. Both KSP32 mRNA levels as well as renal function recovered 14 days after injury. Administration of an endothelin receptor antagonist (SB-209670), known to restore renal function, significantly increased KSP32 expression.

Acute Kidney Injury↗
PubMed1998

Tissue restricted expression of two human Frzbs in preadipocytes and pancreas.

Frzb is a newly discovered family of secreted glycoproteins that function to modulate signaling activity of Wnt. Frzb proteins share sequence homology with the extracellular domain of the Wnt receptor (frizzled) and are capable of binding to Wnt. Thus, Frzb functions to antagonize Wnt activity by sequestering Wnt and preventing its binding to the frizzled receptor. Since the initial identification of bovine and human Frzb, several related members of this family have been isolated from rodent and human. In this paper, we describe the cloning and expression of two human frzb homologues termed hFRP-1b and hFRP-2. These human FRPs share significant homology to mouse sFRP-1 and sFRP-2 (55 and 98% identity at amino acid level, respectively). Northern blot experiments revealed that these Frzb homologues have highly restricted tissue distribution. hFRP-1b is exclusively expressed in pancreatic tissue while high levels of hFRP-2 were found in adipose tissue. In addition, low levels of hFRP-2 were also observed in other tissues including heart, pancreas and muscle. Remarkably, FRP-2 is predominantly expressed in un-differentiated preadipocytes in both rodent and man. The expression of FRP-2 is also significantly reduced in fat pads from obese mice. Taken together, these data indicate that distinctive members of the Frzb family exhibit different expression patterns in vivo, suggesting their ability to modulate diverse aspects of Wnt signaling. The expression and dysregulation of sFRP-2 in fat and obesity also suggest a potential roles on the Wnt signaling pathway in the pathology of obesity and related metabolic diseases. Molecular cloning and expression of these Frzbs will allow detailed molecular and biochemical analysis of Wnt-Frzb interaction and their impact on Wnt-Frizzled receptor signal transduction.

3T3 Cells↗
PubMed1998

Activation of glomerular mesangial cells by hepatocyte growth factor through tyrosine kinase and protein kinase C.

Hepatocyte growth factor (HGF) induces mitogenesis, chemotaxis, and tubule formation in renal epithelial cells. This study examined the effects of wortmannin and protein kinase C (PKC) inhibitors on HGF-mediated changes in metabolic activity in glomerular mesangial cells and renal epithelial carcinoma A498 cells. The extracellular acidification rate of transformed mouse glomerular mesangial cells and A498 cells was measured as an index of metabolic activity with a microphysiometer. HGF increased the acidification rate of mesangial cells and A498 cells in a concentration-dependent fashion that was inhibited completely by the tyrosine kinase inhibitor tyrophostin-23 (100 microM). The PKC inhibitors RO-32-0432 and SKF-57048 also inhibited HGF-induced acidification. The IC50 values for SKF-57048 were 59 +/- 2 and 20 +/- 10 nM in mesangial cells and A498 cells, respectively (P < 0.05). 12-O-Tetradecanoylphorbol 13-acetate (TPA), a phorbol ester that activates PKC, increased acidification in mesangial and epithelial cells similar to HGF. Wortmannin, an inhibitor of phosphatidylinositol (PI) 3-kinase (IC50 value 1-10 nM), inhibited HGF-induced acidification with an IC50 of 93 +/- 31 and 9 +/- 1 nM in mesangial and A498 cells, respectively (P < 0.05). In contrast, there was no significant difference in the IC50 value of wortmannin for epidermal growth factor (EGF)-induced acidification between mesangial and A498 cells (23 +/- 9 vs 14 +/- 1 nM, respectively). Because the IC50 value for wortmannin in inhibiting HGF but not EGF-induced acidification was an order of magnitude higher in mesangial cells than in epithelial A498 cells, a wortmannin-sensitive PI 3-kinase pathway may not be involved in HGF-mediated acidification in mesangial cells.

Androstadienes↗
PubMed1997

Infection and pathogenicity of chimeric simian-human immunodeficiency viruses in macaques: determinants of high virus loads and CD4 cell killing.

Chimeric simian-human immunodeficiency viruses (SHIVs) carrying envelope glycoproteins derived from a T cell-macrophage dual-tropic primary isolate (human immunodeficiency virus type 1 [HIV-1] strain DH12) were constructed. When inoculated into macaque monkeys, SHIV(MD14) carrying simian immunodeficiency virus-derived nef established significantly higher virus loads than did SHIV(MD1), which contains the HIV-1 nef gene. Three patterns of CD4 cell depletion were observed in infected monkeys: exponential and irreversible loss to undetectable levels within 10 weeks of infection; marked reduction during acute infection followed by partial recovery and stabilization (lasting from 10 weeks to > 1 year), with a later decline to undetectable levels in some animals; and a transient loss during acute infection. The induced immunodeficiency was accompanied by CD4 cell counts of < 50 cells/microL and was associated with Pneumocystis carinii pneumonia, cytomegalovirus meningoencephalitis, lymphoid depletion, and thymic atrophy.

Amino Acid Sequence↗
PubMed1996

Requirement for increased IL-10 in the development of B-1 lymphoproliferative disease in a murine model of CLL.

Malignant B-1 cells derived from NZB mice, a murine model of spontaneous autoimmunity and B cell lymphoproliferative disease, produce significantly higher levels of IL-10 mRNA than normal B-1 or B cells. IL-10 may act as an autocrine growth factor for the expansion of malignant B-1 cells. In order to determine if elevated endogenous production of IL-10 was a required element for the malignant transformation of B-1 cells in NZB mice, backcross animals were studied for the linkage between elevated IL-10 expression and the presence of lymphoid malignancy. The phenotypes of aged (NZB x DBA/2)F1 x NZB animals were determined and a strong correlation was found between the elevated levels of IL-10 mRNA and the development of B-1 malignant clones. In contrast, an increased level of IL-10 message was not associated with elevated serum IgM or the presence of anemia or reticulocytosis which is mainly seen in response to autoantibody production. These results indicate that, at least in NZB, the autoimmunity and lymphoproliferation phenotypes are not linked genetically. IL-10 may enhance proliferation and the development of B-1 cell malignancy rather than antibody production by the B-1 cell subpopulation. Thus, IL-10 plays an important role in B-1 malignancies, and downregulation of IL-10 could be a likely site for intervention in B cell malignancies.

Animals↗
PubMed1996

Myopathy and spontaneous Pasteurella pneumotropica-induced abscess formation in an HIV-1 transgenic mouse model.

In an effort to augment human immunodeficiency virus type 1 (HIV-1) gene expression in transgenic mice, an infectious proviral DNA clone was modified by deleting the two NF kappa B binding sites and some adjacent upstream LTR sequences and replacing them with the core enhancer of Moloney murine leukemia virus (MLV). Two independent lines of MLV/HIV transgenic mice were established that expressed HIV-1-specific RNA in lymphoid tissue, striated skeletal muscle, and the eye lens. Heterozygous animals from each transgenic line spontaneously developed an inflammatory disease of the eye associated with the production of copious amounts of purulent lacrimal secretions beginning at 2 weeks of age. Periorbital abscess formation became grossly apparent by 2 months of age and Pasteurella pneumotropica was cultured from the harderian glands and conjunctival surfaces of many of the MLV/HIV animals but not their nontransgenic, cohabiting littermates. This gram-negative commensal bacterium has been previously associated with a similar disease phenotype in immunocompromised (e.g., nude mice) rodent colonies. MLV/HIV mice developed normally until 15 weeks of age, when weight loss and wasting occurred, culminating in premature death (as earlier as 6 months of age). The cachexia was associated with an initially focal and subsequently progressive myopathy, coinciding with age-related increases of HIV gene expression in muscle.

Abscess↗
PubMed1996

Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse.

Targeted disruption of the transforming growth factor-beta 1 (TGF-beta 1) gene in mice results in the development of a massive multifocal inflammatory disease in many tissues. Because no detectable pathogen was identified, we examined whether autoimmune mechanisms played a role in initiating or maintaining the inflammatory disease. The serum of TGF-beta 1 knockout mice contained elevated titers of antibodies to nuclear antigens (ssDNA, dsDNA, Sm, and RNP) as well as reactivity against the 16/6 idiotype (16/6 Id). In addition, Ig deposits were detected in renal glomeruli of TGF- beta 1 knockout mice. Transplantation of TGF-beta 1 knockout hematopoietic cells into normal irradiated recipients resulted in a similar profile of autoantibody production as well as in the induction of inflammatory lesions. Our results describe autoimmune activity that ensues when the TGF-beta 1 cytokine is absent.

Animals↗
PubMed1988

Development of disease and virus recovery in transgenic mice containing HIV proviral DNA.

Transgenic mice containing intact copies of the human immunodeficiency virus (HIV) proviral DNA were constructed. Founder animals were not viremic for HIV and remained healthy during a 9-month observation period. After being mated with nontransgenic animals, one founder mouse (No. 13) gave rise to F1 progeny that developed a disease syndrome characterized by marked epidermal hyperplasia, lymphadenopathy, splenomegaly, pulmonary lymphoid infiltrates, growth retardation, and death by day 25 of life. Infectious HIV, indistinguishable from parental virus by immunoblot analysis, was recovered from the spleen, lymph nodes, and skin of five of five affected animals.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Cell proliferative response to vaccinia virus is mediated by VGF.

VGF, a polypeptide encoded by vaccinia virus, shares amino acid sequence homology and functional properties with cellular growth factors EGF and TGF-alpha. The availability of a VGF minus (VGF-) virus mutant has enabled us to examine the role of VGF in the replication of virus in vitro and in vivo. Studies in vitro with A431 cells (high EGF receptor density) showed that VGF+ wild-type virus induced the rapid formation of a focus of infection (not a plaque) which could be blocked by a monoclonal antibody to the EGF receptor. In vivo experiments with chicken embryos indicated that VGF+ virus stimulated the growth of ectodermal and entodermal cells of the chorioallantoic membrane. At early times, the majority of proliferating cells contained no detectable virus antigen, indicating that cell growth preceded infection and was a consequence of VGF secretion. Relative to VGF- virus, VGF+ virus produced lesions which contained more proliferating cells, more virus antigen, and increased amounts of infectious progeny. Secretion of VGF thus explains the conundrum of a nontransforming, strongly cytopathic virus inducing a hyperplastic cell response.

Amino Acid Sequence↗
PubMed1981

Development and aging of cholinergic synapses. V. Changes in nicotinic cholinergic receptor binding in ciliary ganglia and irises of the chicken.

In order to study possible age-dependent changes in the number of cholinergic binding sites, we have examined alpha-bungarotoxin (ABTX) binding in the ciliary ganglion and iris of the chicken from 3 months after hatching (a.h.) to 5 years of age and have compared it to acetylcholinesterase (AChE) activity and acetylcholine (AChE) levels. In ciliary ganglia the amount of ABTX binding per ganglion increases 16-fold between 3 and 7 months, after which it returns almost to the 3-month level, at 1.3 years. It then remains virtually unchanged to 5 years. A similar pattern is observed in the amount of binding per protein. ACh levels and AChE activity show a different pattern than ABTX binding. In the iris the amount of ABTX binding remains constant between 3 months and 1.3 years and then it increases 1.6-fold up to 3 years. This period is followed by a decrease to 5 years. The amount of ABTX binding per protein which has increased continuously in the iris from the period following hatching up to 7 months, decreases continuously from 7 months to 5 years. In the iris, both ACh levels and AChE activity per protein follow a pattern which is similar to ABTX binding, decreasing from 3 months to 2 years and then remaining relatvely unvaried between 2 and 6-7 years. Our results suggest that a decrease in receptor number begins during early adulthood in the ganglia, whereas this event occurs at a later stage in the iris. However, the total amount of ABTX binding is still relatively high at late stages. These results support our view that the presynaptic component is more affected by the aging process than the postsynaptic component.

Acetylcholine↗
PubMed1980

Age dependent changes in choline uptake of the chick iris.

The kinetics of the uptake of choline, the rate-limiting substrate in the in vivo synthesis of acetylcholine, were studied during the period 1--7 years in the iris of the chick. These changes were correlated to the endogenous levels of acetylcholine and choline in the same organ. Vmax values per iris decrease significantly at 5 years and continue to decrease at 7 years, to 64% and 37% of the one year value, respectively. If the variation in Vmax is calculaed per protein the decline is 34% between 1 and 5 years. Km does not change significantly during the period 1--7 years. Total acetylcholine and choline levels follow a similar trend, decreasing progressively from 1 to 7 years. Sensitivity to hemicholinium (5.5 X 10(-5) M) decreases significantly between 5 days of incubation (d.i.) and 5 years. Inhibition by ouabain (10(-4) M) shows an opposite trend, increasing significantly from 20% at 5 d.i. to 52% at 3 months. At 5 years sensitivity to ouabain is the same as at 3 months. Nardependence decreases significantly between 5 d.i. and 5 years but no significant changes are seen between 5 d.i. and 3 months. Uptake at 27 degrees C decreases from 59% of control at 5 d.i. to 45% at 3 months, and is not changed at 5 years. Our observations suggest that the effect of aging on peripheral cholinergic neurons is not generalized, but is specifically directed toward the neuronal periphery (terminals) as opposed to cell bodies.

Acetylcholine↗
PubMed1980

Development and aging of cholinergic synapses. IV. Acetylcholinesterase and choline acetyltransferase activities in autonomic ganglia and iris of the chick.

Age-related changes in the activities of choline acetyltransferase an acetylcholinesterase in avian sympathetic ganglia, ciliary ganglia and iris have been determined throughout the posthatching life span. Kinetic characteristics of these enzymes have been analyzed in the nerve terminals in the iris from early embryonic stages to the latest periods of life. Enzyme activities and kinetics have been related to each other and also to the endogenous levels of acetylcholine. The regulation of the biosynthetic mechanism for acetylcholine through choline uptake and choline acetyltransferase activity in the developing nerve terminal have been examined. The activities of both enzymes in all tissue are reduced at later ages, which is referred to declines in Vmax, as the Km values do not vary significantly at any age. Declines with age are most pronounced in the iris, both in choline acetyltransferase activity and Vmax and in acetylcholine levels, supporting our view of the peripheral autonomic nerve terminal as a major locus for the effects of aging on the peripheral nervous system.

Acetylcholinesterase↗
PubMed1978

Erythrokinetics and ferrokinetics of a viral-induced murine erythroblastosis.

A variant of Rauscher leukemia virus, designated RLV-A, induced a slow progressive impairment of erythropoiesis in BALB/c mice. Identified in this study were a shortened red cell 51-cr half-time, anemia with indices showing minimal but significant hypochromia, ineffective erythropoiesis, and infiltration of the liver, spleen, and peripheral blood with erythroid pecursors. Ferrokinetic studies indicated a normal plasma iron turnover in infected mice but a decreased red cell iron turnover. Large amounts of 59Fe were taken up by the enlarged liver and spleen. Peak splenic heme 59Fe synthesis was delayed 12 hr in the infected mice. The substantial increase in the splenic intraerythrocytic nonheme iron pool and the hypochromic indices indicate a process analogous to that seen in the sideroblastic anemias. The disease produced by this RLV-A variant may prove useful for studying various aspects of the preleukemic sideroblastic anemias and DiGuglielmo syndrome.

Anemia↗
PubMed1975

Target cell of the polycythemia-inducing Friend virus: studies with myleran.

A single injection of Myleran reduced the pluripotent hematopoietic stem cell, i.e., colony forming unit(s) (CFU), and the erythropoietin-responsive cell (ERC) in polycythemic mice to around 0.5% that of the controls. Repeated injections of erythropoietin (EP) restored ERC populations, whereas the CFU remained at very low levels. This selective action of Myleran and EP in polycythemic mice seemed to be a good approach for the study of oncogenic action of Friend virus on target cells. When the CFU and ERC compartments were decreased, practically no response to the virus was obtained. When there was an appreciable ERC population present with decreased CFU, leukemogenesis still occurred (as judged by the increased spleen weight). This result was in proportion to the dose of EP, i.e., stimulation of the ERC or closely related cells.

Animals↗
PubMedDate not supplied

Evaluation of a prepared childbirth program.

A study was undertaken to ascertain what effects on the outcome of labor and delivery could be attributed to a prepared childbirth program. Three tables are included setting forth statistical relationships. The basic conclusion was that more than five hours of structured prenatal education has a positive impact on maternal-child health.

Delivery, Obstetric↗