Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 55-year-old man was admitted because of weakness in the legs of a few days duration. Neurological examination revealed paraparesis, ataxia of the left limbs, superficial hypoesthesia below the T-10 dermatome level and urinary retention. The antibody titers to human T-lymphotropic virus type I (HTLV-I) were x640 in the serum and x16 in the cerebrospinal fluid (CSF). The HTLV-I gag proteins, p19, p24, p46 and p53 were identified by Western blotting analysis of the serum and CSF. The CSF contained 691 white cells/c.mm; protein, 260 mg/dl; IgG, 84 mg/dl; and IgG index, 2.49. Although the paraparesis and urinary retention disappeared within 10 days, he developed right uveitis which responded well to corticosteroid treatment. With improvement of the sensory impairment, cerebellar signs and CSF pleocytosis as well as uveitis, he was discharged eight weeks after admission. HTLV-I uveitis is a recently established disease entity. The case emphasizes the need to test blood and CSF for HTLV-I antibodies if patients developed myelopathy and cerebellar signs of acute onset, especially when associated with uveitis.
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PMID:Acute myelopathy and cerebellar signs associated with uveitis with positive serum and cerebrospinal fluid antibodies to HTLV-I. 770 52

Cowden syndrome is an autosomal dominant condition of multiple hamartomas. Patients with this phakomatosis have an increased risk of breast cancer and thyroid tumours. Lhermitte-Duclos disease is usually a sporadic condition of cerebellar ganglion cell hypertrophy, ataxia, mental retardation, and self-limited seizure disorder. We describe a three generation family with Cowden syndrome and Lhermitte-Duclos disease. Karyotyping performed on the peripheral lymphocytes of the proband and her affected mother showed a 46,XX complement. Single strand conformational polymorphism analysis failed to show any germline p53 mutations as a cause of the syndrome in this family.
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PMID:Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy? 807 72

A family history for breast cancer appears to be a major risk factor for breast cancer. It has been estimated that 5% of all breast cancers are hereditary. In the last five years much progress has been made in the identification of genes responsible for breast cancer. Much interest is focused on the BRCA-1 gene, which is associated with early onset breast and ovarian cancers. Heterogeneity within and across families in the pattern of cancer susceptibility has suggested that different susceptibility alleles may exist. The BRCA-1 gene has been cloned but the function of its product has not been determined. BRCA-1 mutations seem not to be involved in sporadic breast cancer. A second breast cancer susceptibility gene, BRCA-2, has been localized to chromosome 13q12-q13 but has not been identified as yet. Loss of heterozygosity of 13q is observed in 25% of sporadic breast tumors, which indicates that BRCA-2 might be a tumor suppressor gene. BRCA-2 confers only a low ovarian cancer risk. The TP53 gene has also been associated with breast cancer but to a much more limited extent than BRCA-1. Germline TP53 mutations have been found in patients with familial breast cancer. Other genes that have been associated with breast cancer risk are the androgen receptor (AR) gene and the ataxia teleangiectasia (AT) gene. The importance of the AR gene appears to be limited but the AT gene might be of considerable importance. It is to be expected that additional breast cancer susceptibility genes will be identified in the near future.
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PMID:Genes responsible for familial breast cancer. 888 Aug 69

The development of a normal cell into a tumor cell appears to depend in part on mutations in genes that normally control cell cycle and cell death, thereby resulting in inappropriate cellular survival and tumorigenesis. ATM ("mutated in ataxia-telangiectasia") and p53 are two gene products that are believed to play a major role in maintaining the integrity of the genome such that alterations in these gene products may contribute to increased incidence of genomic changes such as deletions, translocations, and amplifications, which are common during oncogenesis. p53 is a critical participant in a signal transduction pathway that mediates either a G1 arrest or apoptosis in response to DNA damage. In addition, p53 is believed to be involved in the mitotic spindle checkpoint and in the regulation of centrosome function. Following certain cytotoxic stresses, normal ATM function is required for p53-mediated G1 arrest. ATM is also involved in other cellular processes such as S phase and G2-M phase arrest and in radiosensitivity. The understanding of the roles that both p53 and ATM play in cell cycle progression and cell death in response to DNA damage may provide new insights into the molecular mechanisms of cellular transformation and may help identify potential targets for improved cancer therapies.
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PMID:p53 and ATM: cell cycle, cell death, and cancer. 911 62

The gene termed p53 is one of the most extensively studied for the past 18 years and the amount of literature published on this gene reflects its relevance in the field of molecular oncology; thus, loss or mutation of this oncosuppressor gene is probably the molecular lesion most frequently observed in human tumors. The aim of this minireview is to report, discuss, and interpret some recent observations on this topic: (I) The relationship with the Ataxia-Telangectasia gene and with the signaling enzyme phosphatidylinositol 3-kinase (PI3K). (II) The relationship between DNA damage, p53, and sensitivity to anticancer therapies. (III) The gain of function caused by mutations that transform the oncosuppressor p53 gene into a dominant transforming oncogene and (IV) The phosphorylative regulation of p53 and its relationship with the mitogenic signaling cascade involving protein kinase C and tumor promoters.
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PMID:The old and the new in p53 functional regulation. 936 92

The basic steps of the eukaryotic cell cycle process have been known for almost half a century. The development of the molecular biological methods allowed the identification of the cell cycle regulatory genes and their products. The cycline-dependent kinases as catalytic subunits of the multiprotein nuclear enzyme complexes, regulate the cell cycle machinery in a direct way in complex with the cyclins which appear periodically and the negatively modulating cyclin inhibitors. To assure strategy of the cell for global survival during the DNA injury, the Ataxia Teleangiectasia Mutator gene function has a supervisory role in the coordination and parallel activation of the checkpoint control, p53 tumor suppressor gene, GADD45 protein and of the DNA repair, thus prevents the activation of the cell death program. The outlined regulator system gives an opportunity to explain some of the phenomena related to tumor biology and pharmacology.
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PMID:[Regulation of the cell cycle]. 954 97

When cells are exposed to ionizing radiation, they initiate a complex response that includes the arrest of cell cycle progression in G1 and G2, apoptosis and DNA repair. DNA is an important subcellular target of ionizing radiation, but oxydative damage to plasma membrane lipids initiates signal transduction pathways that activate apoptosis and that may play a role in cell cycle regulation. How is DNA damage converted into intracellular signals for cell cycle arrest? The ataxia telangectasia mutant (ATM) protein and/or the DNA-dependent protein kinase (DNA-PK), that are both activated by DNA damage, may initiate cell cycle arrest by activating the p53 tumor suppressor protein. The p53 protein acts as a transcription factor and regulates expression of several components implicated in pathways that regulate cell cycle progression. The best known, p21WAF1/CIP1 protein, is an inhibitor of cyclin-dependent kinases (CDK), a family of protein kinases known as key regulators of cell cycle progression. p21WAF1/CIP1 was shown to be able to inhibit several CDK, but is most effective toward G1/S cyclins. Other CDK inhibitors, p27KIP1 and p15INK4b are activated by irradiation and contribute to the G1 arrest. Moreover, radiation-induced G2 arrest was shown to require inhibitory phosphorylation of the kinase cdc2 via an ATM-dependent pathway. Mutations in cell cycle regulatory genes are common in human cancer and cell cycle regulatory deficiency can lead to increase resistance to ionizing radiation in cancer cells. The major function of p53-dependent G1 arrest may be elimination of cells containing DNA damage whereas G2 arrest following radiation has been shown to be important in protecting cells from death. Cell cycle checkpoints offer a new set of potential targets for chemotherapeutic compounds, especially the G2 checkpoint. Thus, abrogation of the G2 checkpoint with methylxanthines such as caffeine or protein kinase inhibitors such as staurosporine and UCN-01 (7-hydroxystaurosporine) was found to sensitize cells to ionizing radiation. These data did not lead to clinical applications, but confirm targeting of the G2 checkpoint may be an important strategy for cancer therapy.
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PMID:[Cell cycle regulation after exposure to ionizing radiation]. 1034 40

Ionizing radiation activates not only signalling pathways in the nucleus as a result of DNA damage, but also signalling pathways initiated at the level of the plasma membrane. Proteins involved in DNA damage recognition include poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, p53 and ataxia- telangiectasia mutated (ATM). Many of these proteins are inactivated by caspases during the execution phase of apoptosis. Signalling pathways outside the nucleus involve tyrosine kinases such as stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), protein kinase C, ceramide and reactive oxygen species. Recent evidence shows that tumour cells resistant to ionizing radiation-induced apoptosis have defective ceramide signalling. How these signalling pathways converge to activate the caspases is presently unknown, although in some cell types a role for calpain has been suggested.
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PMID:Molecular mechanisms of ionizing radiation-induced apoptosis. 1036 Dec 59

Invertebrate cells lack the p53 recombination checkpoint but contain mobile DNA sequences that transpose by a mechanism in part shared with excision of the V(D)J recombination signal sequences (RSS). In this work, inversion, deletion, and duplication of sequences associated with an invertebrate C. elegans Tc6 element is described. The structure of this C. elegans sequence and other dispersed Tc6 elements suggests that covalently closed 'hairpin' structures are not unique to excision of the V(D)J RSS by the RAG proteins, but rather can be generated by transposases at transposon termini leading to characteristic inversion and duplication events. Comparative analysis of recombination events at invertebrate sequences resembling the vertebrate V(D)J RSS may be useful in understanding V(D)J recombination-mediated recombination events in malignant vertebrate cells or genetic diseases such as ataxia telangectasia, in which the p53 recombination checkpoint is defective.
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PMID:Comparative analysis of invertebrate Tc6 sequences that resemble the vertebrate V(D)J recombination signal sequences (RSS). 1044

Ataxia-telangiectasia mutated (ATM) is the product of the gene mutated in the human genetic disorder ataxia-telangeictasia (A-T). It is a 370 kDa protein that is a member of the phosphatidyl inositol 3-kinases superfamily. A-T cells and those derived from Atm-/- mice are characterized by hypersensitivity to ionizing radiation and defective cell cycle checkpoints. Defects are observed at all cell cycle checkpoints in A-T cells post-irradiation including the G1/S interface where ATM plays an important role in the activation of the tumour suppressor gene product p53. Activation leads to the induction of p21/WAF1, inhibition of cyclin-dependent kinase activity, failure to phosphorylate key substrates such as the retinoblastoma protein and consequently G1 arrest. ATM also plays an important role in the regulation and surveillance of meiotic progression. Absence of ATM gives rise to a spectrum of defects including immunodeficiency, neurodegeneration, radiosensitivity and cancer predisposition. It is clear that a better definition of the role of ATM in DNA damage recognition, cell cycle control and cell signalling may assist in the treatment of the progressive neurodegeneration in this syndrome.
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PMID:ATM: the product of the gene mutated in ataxia-telangiectasia. 1046 28


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