Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Fanconi anemia group C gene (FAC) encodes a 63-kDa protein that plays a role in the growth and differentiation of hematopoietic progenitor cells and in cellular resistance to bifunctional cross-linking agents. The function of the gene product is unknown, as are the factors that govern expression of the gene itself. Seeking to associate a function of this protein with a general metabolic pathway, we attempted to identify factors that induce or repress expression of the gene encoding it. Using two plasmids from which mutant FAC mRNA molecules were transcribed in vitro to serve as competitor mRNAs in quantitative-competitive reverse transcriptase-polymerase chain reaction analysis and novel rabbit antisera raised to recombinant FAC proteins, we quantified gene expression in human hematopoietic cells. We determined that FAC is expressed constitutively in unstimulated normal peripheral blood mononuclear leukocytes, in Epstein-Barr virus (EBV)-transformed B lymphocytes, and in the factor-dependent human myeloid leukemic cell line MO7e at levels of approximately 2000, 200, and 200 FAC mRNA molecules/cell, respectively, and in CD34+ cells from normal human bone marrow at approximately 2000 FAC mRNA molecules/cell. Neither mRNA nor protein increased in any of the cells studied after exposure to mitomycin C, diepoxybutane, hydrogen peroxide, gamma radiation, heat, transforming growth factor-beta, or interferon-gamma. Using these sensitive methods, we confirmed that the FAC gene is constitutively expressed, even in the face of extracellular factors for which the gene product is a known effector of resistance. We conclude that the protective functions of the FAC gene product do not depend upon stressor-induced FAC gene expression.
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PMID:Expression of the Fanconi anemia group C gene in hematopoietic cells is not influenced by oxidative stress, cross-linking agents, radiation, heat, or mitotic inhibitory factors. 943 May 10

Exposure of hematopoietic progenitor cells (HPC) from mice and humans with Fanconi anemia group C (FAC) to interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF-alpha) at doses too low to inhibit growth of normal HPC induces profound apoptotic responses. Because the IFN-gamma hypersensitivity of cells lacking the FAC protein is mediated, in part, through priming of the Fas pathway, and because several other members of this family are capable of inducing apoptosis either alone or in concert with each other, we tested the hypothesis that IFN-gamma induces increased expression of members of the TNF receptor (TNFR) superfamily in cells nullizygous for the FAC gene. Using isogenic human Epstein-Barr virus-transformed lymphoblast cell lines and c-kit+ bone marrow cells from mice with inactivating mutations of the FAC locus, we quantified mRNA levels by reverse transcriptase polymerase chain reaction and surface expression of the gene products by flow cytometry of TNFR1, TNFR2, Fas, CD30, CD40, and nerve growth factor receptor. We found that neither constitutive nor IFN-gamma-induced expression of these receptors was influenced by the absence of a functional FAC gene product, and expression of these receptors was not suppressed in nullizygous cells complemented with the normal FAC cDNA. We conclude that, although exaggerated apoptotic responses in FAC-deficient cells are at least partially mediated through activation of members of the TNFR superfamily, the normal FAC protein does not function as a direct suppressor of this family of molecules and inactivation of FAC does not augment expression of these proteins.
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PMID:The Fanconi anemia group C gene product modulates apoptotic responses to tumor necrosis factor-alpha and Fas ligand but does not suppress expression of receptors of the tumor necrosis factor receptor superfamily. 992 38

Although nephrotoxicity of cidofovir and adefovir is well established, no renal side effects have been observed yet with tenofovir, which is the third member of this family. The authors report the case of a patient who had Fanconi syndrome, nephrogenic diabetes insipidus, and acute renal failure during treatment with tenofovir, a nucleotide reverse transcriptase inhibitor that recently has been approved by the Food and Drug Administration for treatment of patients infected with human immunodeficiency virus.
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PMID:Fanconi syndrome and renal failure induced by tenofovir: a first case report. 1246 55

Long-term alterations to body metabolism have become apparent with the prolonged use of antiretroviral nucleoside analogue reverse transcriptase inhibitors (NRTIs). The NRTIs differ in the mechanisms, potency and probably also tissue specificity of mitochondrial toxicity. One group of NRTIs, the so-called "d-drugs" (zalcitabine> didanosine>stavudine) are relatively strong inhibitors of g-polymerase and thus cause a time- and dose-dependent decrease in the intracellular levels of mitochondrial DNA (mtDNA). The most important target organs of d-drugs are the liver, skeletal muscle, peripheral nerves and probably also the subcutaneous adipose tissue of lipoatrophic subjects. Hyperlactataemia may be observed. Zidovudine is an inhibitor of the mitochondrial adenine nucleotide translocator, binds to adenylate kinase and may also be converted into stavudine triphosphate in vivo. Persistent hyperlactataemia, mtDNA depletion and isolated cases of mitochondrial encephalomyopathies have been observed in babies under perinatal exposure with zidovudine. Nucleotide analogues such as tenofovir are avidly taken up into renal tubular epithelia. Isolated cases of renal failure and Fanconi syndrome require further investigation. Mitochondrial toxicity cannot yet be adequately monitored and predicted. Drugs with potential additive or synergistic toxicity, such as valproate, should be used with caution. Didanosine interacts with allopurinol, hydroxyurea and ribavirin. In established mitochondrial toxicity, cessation of the offending NRTI remains the most effective therapeutic intervention because vitamin cocktails and l-carnitine have, at best, only a marginal effect.
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PMID:Update on mitochondrial toxicity: where are we now? 1283 62

An HIV-infected man taking long-term zidovudine and didanosine presented with a polyphenotypic expression of nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial toxicity. Clinical features included lactic acidosis, myopathy, Fanconi-type proximal tubulopathy, pancreatic dysfunction, pseudo-obstruction, mega-oesophagus, peripheral sensory neuropathy and osteoporosis. A muscle biopsy showed morphologically abnormal mitochondria and respiratory chain biochemistry revealed marked reductions in the activity of respiratory chain enzymes containing mitochondrial DNA-encoded subunits. Southern blotting showed no mitochondrial DNA depletion and long PCR revealed only minor deletions. Following withdrawal of NRTI therapy, the lactic acidosis, pancreatic dysfunction and Fanconi's tubulopathy rapidly improved. Over the next 6 months there was marked improvement in osteoporosis, myopathy and neuropathy. At this stage, dual protease inhibitors and nevirapine were started. A repeat muscle biopsy 14 months after presentation showed normal morphology and respiratory chain biochemistry was almost normal.
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PMID:Polyphenotypic expression of mitochondrial toxicity caused by nucleoside reverse transcriptase inhibitors. 1292 44

Telomeres represent the nucleoprotein tails of chromosomes that get shortened with each cell division. When the telomere length reaches a critical point, cell senescence and death occur. Telomerase is a reverse transcriptase that counteracts telomere loss by adding telomeric sequences. In patients with acquired aplastic anemia, the mean telomere length (TRF) of peripheral blood leukocytes is generally short when compared to normal controls, without it being clear whether a relationship between TRF and disease severity exists. Additionally, increased telomerase activity (TA) is found in the bone marrow mononuclear cell population (MNCs) of aplastic anemia patients, especially in the chronic form of the disease. Fanconi anemia (FA) patients generally demonstrate increased TA and short telomeres in peripheral blood MNCs, a fact attributed to the high turnover of hematopoietic progenitor cells in combination with direct breakages at telomeric sequences. Furthermore, a strong correlation has been shown between TRF and the severity of aplastic anemia, but not with FA evolution towards myelodysplastic syndrome or acute myeloblastic leukemia. In respect of dyskeratosis congenita (DC), a disease of either X-linked or autosomal dominant/recessive inheritance which is characterized by premature ageing of highly regenerative tissues, studies have been carried out in order to elucidate whether the X-linked DC is caused by a defect in ribosomal RNA processing and/or telomere maintenance. Finally, the direct genetic link established between DC pathogenesis and short telomeres may lead to the development of new therapeutic protocols for diseases characterized by short telomere length and subsequent genomic instability.
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PMID:Telomere length variation and telomerase activity expression in patients with congenital and acquired aplastic anemia. 1503 32

We report a case of Fanconi syndrome associated with the use of tenofovir disoproxil fumarate, a nucleotide reverse transcriptase inhibitor used in the treatment of HIV infection. A 56-year-old HIV-infected man was admitted to the hospital with a chief complaint of severe, progressive weakness. His HIV infection was well controlled by antiretroviral therapy; other medical problems included hepatitis C and chronic renal insufficiency. About 2 weeks before presentation, the patient had received an influenza vaccination, which was followed by a generalized viral syndrome of several days' duration. Next, weakness developed and culminated in an inability to walk; this prompted the patient's presentation at the hospital. Urine chemistry, electrolyte panel, and clinical presentation were consistent with Fanconi syndrome, a generalized proximal tubular dysfunction involving proteins, glucose, uric acid, and electrolytes. Along with our Case Report, we review 25 cases of Fanconi syndrome previously reported in the literature.
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PMID:Fanconi syndrome associated with use of tenofovir in HIV-infected patients: a case report and review of the literature. 1604 78

Tenofovir, a new nucleotide reverse transcriptase inhibitor that has good antiviral activity against drug-resistant strains of HIV, is structurally similar to cidofovir and adefovir and seems to be less nephrotoxic. Nephrotoxicity of cidofovir and adefovir is well established and they have been associated with increase for acute renal insufficiency due to tubular toxicity, possibly induced via mitochondrial deplection. Tenofovir has little mithocondrial toxicity in in vitro assays and early clinical studies. However some cases of renal tubular dysfuntion and renal failure related to tenofovir treatment have been published recently. Increased plasma concentrations of didanosine were observed after the adition of tenofovir and protease inhibitors can interact with the renal transport of organic anions leading to proximal tubular intracellular accumulation of tenofovir, yield Fanconi syndrome-type tubulopathy. We present a case in wich acute renal failure and proximal tubular dysfunction developed after therapy with tenofovir in a patiente with HIV who had suffered from complications of didanosine treatment. Although nephrotoxicity certainly occurs much less frequently with tenofovir that it does with other nuclotide analogues, use of tenofovir by patients with underlying renal disfuntion, for longer durations and/or associated with didanosine or lopinavir-ritonavir, might be associated with renal toxicity. Patients receiving tenofovir must be monitored for sings of tubulopathy with simple tests such us glycosuria, phosphaturia, proteinuria, phosphoremia and renal function, as well as assessment for signs of mithocondrial toxicity when a nucleoside analogue is being administered, and therapy should be stopped to avoid the risk of definitive renal failure.
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PMID:[Acute renal failure and proximal renal tubular dysfuntion in a patient with acquired immunodeficiency syndrome treated with tenofovir]. 1711 9

The incidence and prognostic relevance of bone marrow (BM) and leukapheresis (PBPC) tumor cell contamination (TCC) in breast cancer patients is still to be circumstantiated. We developed a new comprehensive gene expression panel to study cytokeratins (CK), maspin (MAS) and mammaglobin (MAM) as possible predictors of prognosis. Forty-eight patients undergoing high dose chemotherapy (HDCT) and PBPC support were enrolled and analyzed for TCC on 116 PBPC apheresis and 96 BM obtained at basal conditions. All of the patients were evaluated by reverse transcriptase nested PCR (RT-PCR) for MAM and MAS gene expression and by immunocytochemistry (ICC) and nested RT-PCR to evaluate CK expression. PBPC and BM frequency of CK-positive (+) cells was 12-13% by ICC and 71-73% by RT-PCR respectively. Sixty-seven percent of CK ICC+ samples were MAM RT-PCR+ and 89% of them were MAS RT-PCR+. PBPC and BM frequency of MAM+ cells was 21% and 31% respectively, while for MAS+ cells it was 48% and 52% respectively by RT-PCR. After 71 mo median FU, 16 patients (33%) relapsed and 14 (88%) had BM/PBPC TCC. No marker had an impact on overall survival (OS) but MAS expression on BM and MAM expression on PBPC correlated with a statistically significant improved (p=0.05) and worsened RFS (p=0.06) respectively. These data confirm the activity of MAM as a negative prognostic factor and show for the first time that MAS could work as a tumor suppressor gene even in a clinical setting, since it protects from recurrence.
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PMID:A new comprehensive gene expression panel to study tumor micrometastasis in patients with high-risk breast cancer. 1733 35

Tenofovir disoproxil fumarate (TDF) is a commonly used HIV antiretroviral. A relatively uncommon adverse effect of this drug is Fanconi syndrome. What is known about this toxicity, especially in regards to concomitant medication use and outcomes, is limited to isolated case reports and small case series. Therefore, a retrospective review of the FDA Adverse Event Reporting System from 2001 through 2006 was conducted to examine demographics, concomitant medication use, outcomes, and temporal trends in reporting of Fanconi syndrome associated with TDF use. In this large case series of 164 subjects who met the case definition for Fanconi syndrome, the majority (83%) of the subjects received protease inhibitors (PI) with TDF; specifically, 74% of the total received a ritonavir-boosted PI. Didanosine was the most commonly (43%) prescribed nucleoside reverse transcriptase inhibitor (NRTI). The combination of didanosine with boosted PI was frequently observed (34%), and in particular, didanosine plus lopinavir/ritonavir was documented for 22%. Nearly half (46%) of the total were hospitalized. Fracture (2%) and requirement for dialysis (2%) were infrequent while Fanconi syndrome contributed to death in 2% of these subjects. Patients receiving ritonavir-boosted protease inhibitors or didanosine with tenofovir should be closely monitored for development of nephrotoxicity. Although reporting biases and the exclusion of reports with serious confounding conditions likely affected the estimation of outcomes in this case series, severe complications of tenofovir-associated Fanconi syndrome were uncommon.
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PMID:Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. 1826 Aug


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