Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An autopsy case of HTLV-I associated myelopathy (HAM) was reported. The patient was a 55-year-old man from Kagoshima, who had no history of blood transfusion. He was admitted to our hospital because of muscle weakness of legs and dysuria, which having since one month ago. On admission, he was able to walk with assistance, but his legs were severely spastic, and Babinski's sign was positive bilaterally. Superficial sensation was normal, but vibration sense was mildly decreased in his legs. CSF showed mild mononuclear pleocytosis with elevated protein. Myelogram and CT were normal. Serum and CSF antibodies to HTLV-I were positive at titers of X4,096 and X128, respectively by immunofluorescent assay, and specific IgG bands (p19, p24, p28 and p53 in serum and p19, p24, p53 in CSF) were detected by western blot analysis. His paraparesis continued to worsen. He became bed-ridden within 2 months. He was received corticosteroid medication. He regained the ability to walk with assistance, and continued taking corticosteroid. In July 4, 1986, macrohematuria appeared and inoperable transitional cell carcinoma of rt. kidney was found by further examination. Chemotherapy were not effective against the carcinoma and he died on July 21, 1987. Neuropathological findings were summarized as follows: cerebral hemisphere was normal except for mild cellular infiltration in the leptomeninges; lesions consisted in unilateral pyramidal tract of pons & medulla and in partial anterior, posterior and lateral columns of the spinal cord; demyelination with axonal degeneration, marked gliosis, numerous lipid-laden macrophages and mild perivascular infiltration of mononuclear cells in these areas.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[An autopsy case of HTLV-I associated myelopathy (HAM)]. 275 64

Apoptosis may be an important mechanism of cell loss in Alzheimer's disease (AD). Experimentally, apoptosis is preceded by nuclear accumulation of p53, and increased expression of Fas (CD95) antigen. In the present study, quantitative Western blot analysis of postmortem frontal and temporal lobe tissue demonstrated significantly higher mean levels of p53 and Fas in AD relative to age-matched controls. Immunohistochemical staining and in situ apoptosis assays demonstrated increased p53 and Fas expression and DNA fragmentation in overlapping populations of cortical neurons, and cortical and white matter glial cells distributed in regions damaged by neurodegeneration. Double-label immunohistochemical staining studies revealed p53 immunoreactivity in: 1) cortical neurons without tau-immunoreactive neurofibrillary tangles; 2) numerous, but not all tau-immunoreactive neuropil neurites and white matter axons; 3) dystrophic fibrils surrounding amyloid-beta-immunoreactive plaques; and 4) glial cells characterized as A2B5+ protoplasmic astrocytes or oligodendrocytes. The prominent distribution of dystrophic p53-immunoreactive processes around amyloid-beta-containing plaques suggests that amyloid deposits are associated with local neuritic degeneration. In addition, the results suggest that many tau-immunoreactive neuritic processes originate from degenerating (p53) as well as regenerating neurons. Finally, apoptosis of glial cells (A2B5+) required to maintain the functional integrity of axons and dendrites may represent an important pathogenic mechanism of axonal loss and synaptic disconnection in AD.
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PMID:Correlates of p53- and Fas (CD95)-mediated apoptosis in Alzheimer's disease. 939 28

A cDNA microarray analysis indicated that Semaphorin3B (Sema3B), a gene whose product is involved in axon guidance and axonal repulsion, is inducible by p53. Introduction of exogenous p53 into a glioblastoma cell line lacking wild-type p53 (U373MG) dramatically induced expression of Sema3B mRNA. An electrophoretic mobility shift assay and a reporter assay confirmed that a potential p53 binding site present in the promoter region had p53-dependent transcriptional activity. Expression of endogenous Sema3B was induced in response to genotoxic stresses caused by adriamycin treatment or UV irradiation in a p53-dependent manner. Ectopic expression of Sema3B in p53-defective cells reduced the number of colonies in colony formation assays. These results suggest that Sema3B might play some role in regulating cell growth as a mediator of p53 tumor-suppressor activity.
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PMID:Identification of semaphorin3B as a direct target of p53. 1192 94

Loss of axonal contact characterizes Schwann cells in benign and malignant peripheral nerve sheath tumors (MPNST) from neurofibromatosis type 1 (NF1) patients. Tumor Schwann cells demonstrate NF1 mutations, elevated Ras activity, and aberrant epidermal growth factor receptor (EGFR) expression. Using cDNA microarrays, we found that brain lipid binding protein (BLBP) is elevated in an EGFR-positive subpopulation of Nf1 mutant mouse Schwann cells (Nf1(-/-) TXF) that grows away from axons; BLBP expression was not affected by farnesyltransferase inhibitor, an inhibitor of H-Ras. BLBP was also detected in EGFR-positive cell lines derived from Nf1:p53 double mutant mice and human MPNST. BLBP expression was induced in normal Schwann cells following transfection with EGFR but not H-Ras12V. Furthermore, EGFR-mediated BLBP expression was not inhibited by dominant-negative H-Ras, indicating that BLBP expression is downstream of Ras-independent EGFR signaling. BLBP-blocking antibodies enabled process outgrowth from Nf1(-/-) TXF cells and restored interaction with axons, without affecting cell proliferation or migration. Following injury, BLBP expression was induced in normal sciatic nerves when nonmyelinating Schwann cells remodeled their processes. These data suggest that BLBP, stimulated by Ras-independent pathways, regulates Schwann cell-axon interactions in normal peripheral nerve and peripheral nerve tumors.
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PMID:Brain lipid binding protein in axon-Schwann cell interactions and peripheral nerve tumorigenesis. 1261 91

WW domain-containing oxidoreductase WOX1, also known as WWOX or FOR, is a proapoptotic protein and a putative tumor suppressor. Hyaluronidases such as PH-20, Hyal-1 and Hyal-2 induce the expression of WOX1, and hyaluronidases and hyaluronan are involved in the embryonic development. In the present study, we document the expression of WOX1 in the developing murine nervous system. Immunohistochemical analysis revealed that WOX1 was differentially expressed in early dividing cells from all three germ layers from embryonic to perinatal stages. In murine fetuses, WOX1 was present prevalently in the brainstem, spinal cord and peripheral nerve bundles, but its expression decreased after birth. In parallel, the expression of WOX1, as determined by Western blotting, was significantly reduced in the brain stem and spinal cord of adult mice. Notably, high levels of WOX1 immunoreactivity was observed in the neural crest-derived structures such as cranial and spinal ganglia and cranial mesenchyme during the late fetal stage. In the adult brain, WOX1 is abundant in the epithelial cells of the choroids plexus and ependymal cells, while a low to moderate level of WOX1 is observed within white matter tracts, such as axonal profiles of the corpus callosum, striatum, optic tract, and cerebral peduncle. WOX1 is shown to mediate apoptosis synergistically with p53 in vitro. Nonetheless, the expression profiles of WOX1 were found to be similar in both p53 wild type and knockout mice, suggesting that WOX1 expression is not controlled by p53-mediated gene transcription. Taken together, in this study we have shown the expression and distribution of WOX1 in developing and adult murine nervous system. The potential role of WOX1 in the neuronal differentiation is discussed.
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PMID:Expression of WW domain-containing oxidoreductase WOX1 in the developing murine nervous system. 1502 24

Neuronal and glial cell death and traumatic axonal injury contribute to the overall pathology of traumatic brain injury (TBI) in both humans and animals. In both head-injured humans and following experimental brain injury, dying neural cells exhibit either an apoptotic or a necrotic morphology. Apoptotic and necrotic neurons have been identified within contusions in the acute post-traumatic period, and in regions remote from the site of impact in the days and weeks after trauma, while degenerating oligodendrocytes and astrocytes have been observed within injured white matter tracts. We review and compare the regional and temporal patterns of apoptotic and necrotic cell death following TBI and the possible mechanisms underlying trauma-induced cell death. While excitatory amino acids, increases in intracellular calcium and free radicals can all cause cells to undergo apoptosis, in vitro studies have determined that neural cells can undergo apoptosis via many other pathways. It is generally accepted that a shift in the balance between pro- and anti-apoptotic protein factors towards the expression of proteins that promote death may be one mechanism underlying apoptotic cell death. The effect of TBI on cellular expression of survival promoting-proteins such as Bcl-2, Bcl-xL, and extracellular signal-regulated kinases, and death-inducing proteins such as Bax, c-Jun N-terminal kinase, tumor-suppressor gene, p53, and the calpain and caspase families of proteases are reviewed. In light of pharmacologic strategies that have been devised to reduce the extent of apoptotic cell death in animal models of TBI, our review also considers whether apoptosis may serve a protective role in the injured brain. Together, these observations suggest that cell death mechanisms may be representative of a continuum between apoptotic and necrotic pathways.
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PMID:Cell death mechanisms following traumatic brain injury. 1519 35

The experimentally induced cryptorchid mouse model is useful for elucidating the in vivo molecular mechanism of germ cell apoptosis. Apoptosis, in general, is thought to be partly regulated by the ubiquitin-proteasome system. Here, we analyzed the function of two closely related members of the ubiquitin C-terminal hydrolase (UCH) family in testicular germ cell apoptosis experimentally induced by cryptorchidism. The two enzymes, UCH-L1 and UCH-L3, deubiquitinate ubiquitin-protein conjugates and control the cellular balance of ubiquitin. The testes of gracile axonal dystrophy (gad) mice, which lack UCH-L1, were resistant to cryptorchid stress-related injury and had reduced ubiquitin levels. The level of both anti-apoptotic (Bcl-2 family and XIAP) and prosurvival (pCREB and BDNF) proteins was significantly higher in gad mice after cryptorchid stress. In contrast, Uchl3 knockout mice showed profound testicular atrophy and apoptotic germ cell loss after cryptorchid injury. Ubiquitin level was not significantly different between wild-type and Uchl3 knockout mice, whereas the levels of Nedd8 and the apoptotic proteins p53, Bax, and caspase3 were elevated in Uchl3 knockout mice. These results demonstrate that UCH-L1 and UCH-L3 function differentially to regulate the cellular levels of anti-apoptotic, prosurvival, and apoptotic proteins during testicular germ cell apoptosis.
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PMID:Two closely related ubiquitin C-terminal hydrolase isozymes function as reciprocal modulators of germ cell apoptosis in cryptorchid testis. 1546

Alpha-synuclein (alpha-Syn) is enriched in nerve terminals. Two mutations in the alpha-Syn gene (Ala53--> Thr and Ala30--> Pro) occur in autosomal dominant familial Parkinson's disease. Mice overexpressing the human A53T mutant alpha-Syn develop a severe movement disorder, paralysis, and synucleinopathy, but the mechanisms are not understood. We examined whether transgenic mice expressing human wild-type or familial Parkinson's disease-linked A53T or A30P mutant alpha-syn develop neuronal degeneration and cell death. Mutant mice were examined at early- to mid-stage disease and at near end-stage disease. Age-matched nontransgenic littermates were controls. In A53T mice, neurons in brainstem and spinal cord exhibited large axonal swellings, somal chromatolytic changes, and nuclear condensation. Spheroid eosinophilic Lewy body-like inclusions were present in the cytoplasm of cortical neurons and spinal motor neurons. These inclusions contained human alpha-syn and nitrated synuclein. Motor neurons were depleted (approximately 75%) in A53T mice but were affected less in A30P mice. Axonal degeneration was present in many regions. Electron microscopy confirmed the cell and axonal degeneration and revealed cytoplasmic inclusions in dendrites and axons. Some inclusions were degenerating mitochondria and were positive for humanalpha-syn. Mitochondrial complex IV and V proteins were at control levels, but complex IV activity was reduced significantly in spinal cord. Subsets of neurons in neocortex, brainstem, and spinal cord ventral horn were positive for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, cleaved caspase-3, and p53. Mitochondria in neurons had terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive matrices and p53 at the outer membrane. Thus, A53T mutant mice develop intraneuronal inclusions, mitochondrial DNA damage and degeneration, and apoptotic-like death of neocortical, brainstem, and motor neurons.
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PMID:Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. 1639 71

Epidermal melanocytes execute specific physiological programs in response to UV radiation (UVR) at the cutaneous interface. Many melanocytic responses, including increased dendrite formation, enhanced melanogenesis/melanization, and cell cycle arrest impact the ability of melanocytes to survive and to attenuate the UVR insult. Although some of the molecules that underlie these UVR programs are known, a coherent view of UVR-induced transcriptional changes is lacking. Using primary melanocyte cultures, we assessed for UVR-mediated alterations in over 47,000 transcripts using Affymetrix Human Genome U133 Plus 2.0 microarrays. From the 100 most statistically robust changes in transcript level, there were 84 genes that were suppressed >2.0-fold by UVR; among these transcripts, the identities of 48 of these genes were known. Similarly, there were 99 genes that were induced >2.0-fold by UVR; the identity of 57 of these genes were known. We then subjected these top 100 changes to the Ingenuity Pathway analysis program and identified a group of p53 targets including the cell cycle regulator CDKN1A (p21CIP), the WNT pathway regulator DKK1 (dickkopf homolog 1), the receptor tyrosine kinase EPHA2, growth factor GDF15, ferrodoxin reductase (FDXR), p53-inducible protein TP53I3, transcription factor ATF3, DNA repair enzyme DDB2, and the beta-adrenergic receptor ADBR2. These genes were also found to be consistently elevated by UVR in six independent melanocyte lines, although there were interindividual variations in magnitude. WWOX, whose protein product interacts and regulates p53 and p73, was found to be consistently suppressed by UVR. There was also a subgroup of neurite/axonal developmental genes that were altered in response to UVR, suggesting that melanocytic and neuronal arborization may share similar mechanisms. When compared to melanomas, the basal levels of many of these p53-responsive genes were greatly dysregulated. Three genes--CDKN1A, DDB2 and ADRB2--exhibited a trend towards loss of expression in melanomas thereby raising the possibility of a linked role in tumorigenesis. These expression data provide a global view of UVR-induced changes in melanocytes and, more importantly, generate novel hypotheses regarding melanocyte physiology.
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PMID:Expression profiling of UVB response in melanocytes identifies a set of p53-target genes. 1688 33

The neurite outgrowth inhibitor protein Nogo-A has been identified as an inhibitor of axonal regeneration, and Nogo-B as a regulator of vasculature remodeling, but the additional roles of Nogo isoforms, especially Nogo-C, have obtained little attention. Nogo-C is weakly expressed in liver and kidney compared to the high expression in skeletal muscle. Here we detected the weak expression of Nogo-C in human embryonic kidney cell line HEK293, and found that Nogo-C expressed in HEK293 could induce cell apoptosis. Further experiments demonstrated the activation of JNK/SAPK and c-Jun, but not p38 in Nogo-C expressed cells. And JNK-specific inhibitor SP600125 could reduce cell apoptosis induced by Nogo-C. Furthermore, the activation of caspase-3 and PARP, the expression and phosphorylation of p53 were also detected. The data first revealed Nogo-C expressed in HEK293 confers apoptosis by inducing caspase-3 and p53 activation through the JNK-c-Jun-dependent pathway.
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PMID:Human Nogo-C overexpression induces HEK293 cell apoptosis via a mechanism that involves JNK-c-Jun pathway. 1690 19


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