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

Werdnig-Hoffmann disease (WHD) is the most severe clinical type of spinal muscular atrophy characterized by loss of lower motor neurons and paralysis. We examined the hypothesis that disease pathogenesis is based on an inappropriate persistence of normally occurring motor neuron programmed cell death. The diagnosis of WHD was made on the basis of clinical findings, electromyoneurography, and biopsy, and further confirmed by mutation analysis of the survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes using PCR. We used ultrastructural analysis as well as TUNEL and ISEL methods to assess DNA fragmentation, and immunocytochemistry to identify expression of the apoptosis-related proteins bcl-2 and p53. A significant number of motor neurons in the spinal cord of children with WHD were shown to die by apoptosis. As revealed by TUNEL, dying neurons in WHD patients comprised 0.2%-6.4% of the neuron numbers counted. This finding contradicts earlier studies that failed to find such evidence and suggests that early blockade of prolonged motor neuron apoptosis may be a potential therapeutic strategy for WHD.
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PMID:Ultrastructural analysis and TUNEL demonstrate motor neuron apoptosis in Werdnig-Hoffmann disease. 1088 70

A prostatic smooth muscle cell line (PSMC1) was established from the dorsolateral prostate of p53 null mice. The cell line is nontumorigenic when inoculated subcutaneously, under the renal capsule or intraprostatically in syngeneic mice. These cells express alpha-smooth muscle actin (alpha-SMA), indicating their smooth muscle origin, and TGF-beta significantly enhances expression of alpha-SMA. The cells express both androgen receptor (AR) mRNA and protein, and respond mitogenically to physiological concentrations of androgens. PSMC1 cells produce significant amounts of TGF-beta, which stimulates growth by an autocrine mechanism. Dihydrotestosterone (DHT) increases proliferation of PSMC1 cells by promoting TGF-beta secretion. Considering the significant inhibitory effect of TGF-beta on prostatic epithelial cells and its stimulatory effect on the PSMC1 cells, we postulate that TGF-beta produced by prostatic smooth muscle cells may have a paracrine effect on the prostatic epithelium. We also postulate that TGF-beta may be involved in the etiology of benign prostatic hyperplasia (BPH) by stimulating excessive stromal proliferation. Line PSMC1 is the first reported androgen-responsive murine smooth muscle cell line. It will be useful for in vivo and in vitro experiments to study the mechanisms of androgen action on prostatic stroma and for delineating the interactions that occur between prostatic smooth muscle and epithelium that may lead to prostatic diseases such as BPH.
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PMID:Transforming growth factor-beta is an autocrine mitogen for a novel androgen-responsive murine prostatic smooth muscle cell line, PSMC1. 1105 12

Nasal hemangiopericytoma-like (HPCL) tumor is a rare vascular tumor and should be differentiated from typical hemangiopericytomas (HPCs). This study reports the case of an HPCL tumor in a 77-year-old man with histological and immunohistochemical features. After preoperative evaluation of the blood supply, the dark-red right intranasal tumor was resected completely via the right maxillary sinus. The final histopathological diagnosis was HPCL tumor based on several stains: vimentin (+), alpha-SMA (+), etc. Moreover, there were few p53 (+) cells and the Ki-67 and topoisomerase IIalpha labeling indices were both under 5%. These findings indicated that this tumor was a low-grade malignancy. The immunohistochemical investigations used are useful for making the diagnosis of HPCL tumor and determining the treatment, malignancy, and prognosis.
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PMID:Nasal septal hemangiopericytoma-like tumor: a case report with an immunohistochemical study. 1155 60

Mutations in the SMN1 (survival motor neuron 1) gene cause spinal muscular atrophy (SMA). We now show that SMN protein, the SMN1 gene product, interacts directly with the tumor suppressor protein, p53. Pathogenic missense mutations in SMN reduce both self-association and p53 binding by SMN, and the extent of the reductions correlate with disease severity. The inactive, truncated form of SMN produced by the SMN2 gene in SMA patients fails to bind p53 efficiently. SMN and p53 co-localize in nuclear Cajal bodies, but p53 redistributes to the nucleolus in fibroblasts from SMA patients. These results suggest a functional interaction between SMN and p53, and the potential for apoptosis when this interaction is impaired may explain motor neuron death in SMA.
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PMID:A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy. 1170 67

Cholestatic liver injury is caused by hepatocellular apoptosis induced by toxic bile salts. We have studied the effects of a traditional Chinese herbal medicine, Salvia miltiorrhiza, on apoptotic cell death in bile duct-ligated (BDL) rats. We also attempted to clarify the molecular mechanisms of the hepatoprotective effects of S. miltiorrhiza in this animal model. A water extract of S. miltiorrhiza (Sm-X; 200 mg/kg; po) was administered to BDL rats for 10 days. Rats were euthanized and apoptosis was detected in liver tissue by TUNEL staining. Western blot analysis and immunostaining for alpha-smooth muscle actin (alpha-SMA), Bax, Bcl-2, and p53 were performed. Results show that the treatment of BDL rats with Sm-X significantly improved the liver function parameters, although the expression of alpha-SMA, a marker of hepatic stellate cell activation, was not affected. Treatment with Sm-X significantly reduced the number of apoptotic cells. A time-dependent decrease in Bax protein level and an increase in Bcl-2 protein level were observed in BDL rats treated with Sm-X. Immunohistochemical analysis demonstrated that p53 was strongly positive in hepatocyte nuclei of BDL rats but that treatment with Sm-X induced a cytoplasmic sequestration of p53. Taken together, hepatoprotective effects of Sm-X partially ascribe to the antiapoptotic property in hepatocytes. Treatment of Sm-X-induced cytoplasmic sequestration of p53, downregulation of Bax, and upregulation of Bcl-2 protein. This study identifies and delineates signaling factors involved in the antiapoptotic properties of Sm-X and suggests a potential application of S. miltiorrhiza in the clinical management of hepatic disease induced by toxic bile salts following biliary obstruction.
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PMID:Salvia miltiorrhiza inhibits biliary obstruction-induced hepatocyte apoptosis by cytoplasmic sequestration of p53. 1212 60

Autosomal recessive proximal spinal muscular atrophy (SMA) is a severe neurodegenerative disease of childhood causing weakness and wasting secondary to motor neuron dysfunction. Over 97% of cases are caused by deletions or mutations within the survival motor neuron (SMN) gene. The SMN protein is highly expressed within brain, spinal cord and muscle, and is decreased in SMA patients. It has been shown to have an important role in RNA metabolism, but the reason for the specific motor neuron loss is still unclear. We have used a novel antibody array technology to look for differences in the expression patterns of primary muscle cultures from a type II SMA patient and a normal control. A relatively small number of differences were found within a group of proteins that function as both RNA binding proteins and transcription factors. Interactions between a number of these proteins are well established, and three of them bind in turn to p53 which interacts with SMN. A number of the changes were confirmed with western blot analysis both in the primary muscle cultures and in skeletal muscle samples from SMA patients and controls. Changes at the mRNA level were also confirmed with oligonucleotide arrays. These results suggest that a common transcription pathway may be altered in the disease state, and suggests that down-regulation of transcription factors contributes to SMA pathogenesis.
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PMID:Protein expression changes in spinal muscular atrophy revealed with a novel antibody array technology. 1284 76

Proximal spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutations of the SMN1 gene. SMN1 interacts with multiple proteins with functions in snRNP biogenesis, pre-mRNA splicing and presumably neural transport. SMN2, a nearly identical copy of SMN1, produces predominantly exon 7-skipped transcripts, whereas SMN1 mainly produces full-length transcripts. The SR-like splicing factor Htra2-beta1 facilitates correct splicing of SMN2 exon 7 through direct interaction with an exonic splicing enhancer within exon 7. In rare cases, siblings with identical 5q13-homologues and homozygous absence of SMN1 show variable phenotypes, suggesting that SMA is modified by other factors. By analysing nine SMA discordant families, we demonstrate that in all families unaffected siblings produce significantly higher amounts of SMN, Gemin2, Gemin3, ZPR1 and hnRNP-Q protein in lymphoblastoid cell lines, but not in primary fibroblasts, compared with their affected siblings. Protein p53, an additional SMN-interacting protein, is not subject to an SMN-dependent regulation. Surprisingly, Htra2-beta1 is also regulated by this tissue-specific mechanism. A similar regulation was found in all type I-III SMA patients, although at a different protein level than in discordant families. Thus, our data show that reduced SMN protein levels cause a reduction in the amount of its interacting proteins and of Htra2-beta1 in both discordant and non-discordant SMA families. We provide evidence that an intrinsic SMA modifying factor acts directly on the expression of SMN, thus influencing the SMA phenotype. Further insights into the molecular pathway and the identification of SMA modifying gene(s) may help to find additional targets for a therapy approach.
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PMID:Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1. 1452 May 60

Three canine osteosarcoma cell lines were established from spontaneous pelvic and radial osteosarcomas. The cell populations cultured exhibited characteristics of malignancy and consisted of adherent, pleomorphic, mostly large spindle-shaped or polyhedral cells, characterised by the presence of numerous cytoplasmic granules and vacuoles. The main ultrastructural features included the presence of abundant rough endoplasmic reticulum and numerous cytoplasmic vesicles, deposit vacuoles and small cytoplasmic protrusions. Zymography showed that the cell lines produce high levels of MMP-2 and MMP-9, enzymes directly involved in crucial aspects of the metastatic process. Consistent with their osteoblastic lineage and malignant phenotype, all cell lines were immunoreactive to vimentin, osteopontin, PCNA, p53, MMP-2 and MMP-9, while they were negative for cytokeratin, desmin, SMA, Factor VIII, NSE, GFAP, Rb and p21 protein. No retroviral particles or RNA were detected ultrastructurally or with RT-PCR, although the possibility of viral involvement in osteosarcoma cannot be excluded. The new cell lines provide excellent in vitro models that may allow further studies on the pathobiology of canine osteosarcoma to be undertaken.
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PMID:Characterisation of three novel canine osteosarcoma cell lines producing high levels of matrix metalloproteinases. 1519 3

Vimentin expression is a rather rare finding in invasive breast cancer, and is associated with high tumour invasiveness and chemoresistance. It is currently explained by two different biological theories: direct histogenetic derivation from myoepithelial cells, and epithelial-mesenchymal transition (EMT) reflecting the end-stage of breast cancer dedifferentiation. In this study we aimed to obtain further insights into the biological hallmarks of these vimentin-expressing breast cancers. We applied immunohistochemistry for vimentin and 15 other differentiation markers to a series of 364 invasive breast cancer cases, using tissue microarray technology. 7.7% of all tumours expressed vimentin. Almost all of these cases (19/21) were Grade 3 invasive ductal carcinomas, and the majority (13/21) of these were associated with a ductal in situ component. Vimentin expression was also seen in the respective in situ components and correlated positively with the expression of SMA, CD10, CK 5, p53, Mib-1 and EGFR. A negative correlation was seen for the expression of CK 8/18 and the oestrogen receptor. Vimentin-expressing carcinomas revealed a significantly higher average absolute number of cytogenetic alterations per case, but a significantly lower frequency of chromosome 16q losses compared to vimentin-negative cases. Our present results demonstrate that, despite analogies between vimentin-positive breast cancers and myoepithelial cells in their expression of differentiation-related proteins, neither myoepithelial histogenesis nor EMT can exclusively explain the biology of these distinct tumours. This is mainly supported by the significantly higher incidence of vimentin-expressing breast cancers compared to any other myoepithelial breast tumours and the fact that vimentin is already observed in ductal in situ components. We therefore propose the alternative hypothesis that vimentin-expressing breast carcinomas may derive from breast progenitor cells with bilinear (glandular and myoepithelial) differentiation potential.
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PMID:The origin of vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? 1590 73

The protein inhibitor of activated STAT (PIAS) family of proteins has been proposed to regulate the activity of many transcription factors, including signal transducer and activator of transcription proteins (STATs), nuclear factor-kappaB, SMA- and MAD-related proteins (SMADs), and the tumour-suppressor protein p53. PIAS proteins regulate transcription through several mechanisms, including blocking the DNA-binding activity of transcription factors, recruiting transcriptional corepressors or co-activators, and promoting protein sumoylation. Recent genetic studies support an in vivo function for PIAS proteins in the regulation of innate immune responses. In this article, we review the current understanding of the molecular basis, specificity and physiological roles of PIAS proteins in the regulation of gene-activation pathways in the immune system.
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PMID:Regulation of gene-activation pathways by PIAS proteins in the immune system. 1605 53


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