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)

It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations in cells. Thus, in order to understand the process of acquisition of metastatic phenotypes in cancer cells, it is indispensable to identify genes whose alterations accumulate during cancer progression and correlate with metastatic phenotypes of cancer cells. For this reason, we have been searching for genes that are preferentially altered in metastatic lung cancer cells and have activities to regulate their metastatic potentials. In lung cancer, both the p16INK4A/RB and p53 genes are frequently inactivated and are critical determinants for the regulation of cell growth and apoptosis. However, it still remains unclear whether these genes are also involved in the regulation of metastatic potential in lung cancer cells. Recently, we identified a novel myosin family gene, MYO18B, from the chromosome 22q12.1 region which shows frequent loss of heterozygosity in advanced lung cancer, and we found that this gene is inactivated in approximately 50% of lung cancers by deletions, mutations and methylation. Furthermore, restoration of MYO18B expression suppressed anchorage-independent growth of lung cancer cells. Thus, it was indicated that the MYO18B gene is a strong candidate for a metastasis suppressor gene of human lung cancer. Further functional and biological studies of the MYO18B gene will help us understand the molecular pathway of human lung cancer progression.
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PMID:Genetic alterations responsible for metastatic phenotypes of lung cancer cells. 1274 77

Rhabdomyosarcomas derive from the skeletal muscle lineage and harbor a variety of genetic and molecular lesions. However, it is not clear which molecular alterations have a pathogenetic role. We show that activation of the HER-2/neu oncogene coupled with inactivation of the oncosuppressor gene p53 causes rhabdomyosarcoma in mice. At the age of 11-21 weeks, all male mice carrying both genetic lesions developed embryonal rhabdomyosarcomas expressing desmin, myosin, and insulin-like growth factor-II, in the genitourinary tract. Our findings led to the hypothesis that the interaction between HER family genes and the p53 pathway might be involved in the origin of human rhabdomyosarcoma.
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PMID:Development of rhabdomyosarcoma in HER-2/neu transgenic p53 mutant mice. 1278 74

We immunohistochemically compared benign myoepithelial tumors (adenomyoepitheliomas [AMEs]) and metaplastic matrix-producing (MMP-CA) and spindle cell (MSC-CA) carcinomas of the breast to identify helpful diagnostic markers. Normal myoepithelial cells (MECs) consistently expressed cytokeratin, alpha-smooth muscle actin (SMA), myosin, S-100, CD10, and maspin. They were variably positive for vimentin and negative for epithelial membrane antigen (EMA), steroid receptors, p53, and HER-2/neu. MECs in AMEs less frequently expressed CD10 (4/8 [50%]) and myosin (6/8 [75%]) but frequently acquired characteristics of luminal cells, such as expression of EMA (5/8 [63%]) and steroid receptors (5/8 [63%]). No abnormal p53 or HER-2/neu expression was seen in AMEs. MMP-CA and MSC-CA were similar to AMEs in cytokeratin, vimentin, S-100, maspin, and HER-2/neu expression. MMP-CAs expressed less alpha-SMA (2/8 [25%]) and myosin (2/7 [29%]) and lacked estrogen receptor (0/9 [0%]). MSC-CAs were consistently CD10+ (4/4 [100%]) yet failed to express myosin (0/3 [0%]). p53 overexpression was seen frequently in MMP-CAs (4/8 [50%]) and MSC-CAs (1/3 [33%]). Benign myoepithelial mammary tumors differ immunophenotypically from normal MECs; a panel of immunohistochemical markers may be required to establish their myoepithelial origin. A similarly altered myoepithelial phenotype also is characteristic of metaplastic mammary carcinomas. The abnormal expression of oncogenes or antioncogenes, such as p53, may be more useful for distinguishing between those entities than the expression of the classic myoepithelial markers.
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PMID:Benign myoepithelial tumors of the breast have immunophenotypic characteristics similar to metaplastic matrix-producing and spindle cell carcinomas. 1293 44

Mice that lack cardiac muscle alpha-actin die during the perinatal period. Approximately 56% of mice that are homozygous null (-/-) for a functional cardiac alpha-actin gene do not survive to term, and the remainder generally die within 2 wk of birth. We found that there were neither morphologic differences nor differences in the extent of apoptosis between the mutant and normal hearts on embryonic day (E) 12 and E14 of development. However, apoptosis was greater in the hearts of homozygous null mice on E17 and postnatal day 1 when compared with wild-type hearts. The antiapoptotic factor Bcl-x/(L) was localized in regions adjacent to where apoptosis was detected. The distribution patterns of the apoptosis triggering protein p53 were similar to those of apoptotic cells. The growth of the prenatal and postnatal hearts of the cardiac alpha-actin-deficient mice was retarded, and the cytoplasmic filaments were disorganized. Although apoptotic cells were observed in both the atria and ventricles in the hearts of the homozygous null animals, the frequency was greater in the ventricles than in the atria. Our results indicate that the functional and structural disturbances in the mice with a homozygous lack of cardiac alpha-actin seem to be due to disorganized development of acto-myosin filaments in the affected cardiomyocytes. Other actin isoforms cannot compensate for the lack of cardiac alpha-actin, and this seems to induce apoptosis in defective cardiac myocytes, which are not able to cope with the increased workload in the perinatal phase.
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PMID:Cellular disorganization and extensive apoptosis in the developing heart of mice that lack cardiac muscle alpha-actin: apparent cause of perinatal death. 1460 48

There is much interest in recent years in the possible role of different nuclear compartments and subnuclear domains in the regulation of gene expression, signalling, and cellular functions. The nucleus contains inositol phosphates, actin and actin-binding proteins and myosin isoforms, multiple protein kinases and phosphatases targeting Cdk-1 and Cdk-2, MAPK/SAPK, and Src-related kinases and their substrates, suggesting the implication of several signalling pathways in the intranuclear organization and function of nuclear bodies (NBs). NBs include the well-characterized Cajal bodies (CBs; or coiled bodies), the nucleolus, perinucleolar and perichromatin regions, additional NBs best illustrated by the promyelocytic leukemia nuclear bodies [PML-NBs, also named PML oncogenic dots (PODs), ND10, Kr-bodies] and similar intranuclear foci containing multi-molecular complexes with major role in DNA replication, surveillance, and repair, as well as messenger RNA and ribosomal RNA synthesis and assembly. Chromatin modifying proteins, such as the CBP acetyltransferase and type I histone deacetylase, accumulate at PML-NBs. PML-NBs and Cajal bodies are very dynamic and mobile within the nuclear space and are regulated by cellular stress (heat shock, apoptosis, senescence, heavy metal exposure, viral infection, and DNA damage responses). NBs strongly interact, using signalling mechanisms for the directional and ordered traffic of essential molecular components. NBs organize the delivery and storage of essential RNAs and proteins that play a role in transcription, pre-mRNA biosynthesis and splicing, and the sequestration and/or degradation of regulatory proteins, such as heterogenous nuclear ribonuclear proteins (hnRNPs), p53, Rb1, CBP, STAT3, and others. The objective of this review is to summarize some aspects of these nuclear structures/bodies/domains, including their proposed roles in cellular signalling and in human diseases, mainly neurodegenerative disorders and cancer.
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PMID:Nuclear bodies and compartments: functional roles and cellular signalling in health and disease. 1524 4

Previous studies on skeletal muscle differentiation showed that myogenesis is regulated by extracellular signal-regulated kinases (ERK-1/-2) and p38 mitogen activated kinase (MAPK) pathways. Present study shows that c-Jun NH2-terminal protein kinase (JNK) activities were up regulated during skeletal muscle differentiation in rat skeletal muscle L6E9 cells, as determined by Western immunoblot of differentiating cells probed with anti-phospho-JNK antibody. Inhibition of JNK activities by JNK inhibitor II drastically inhibited differentiation as determined by decreased myosin, myogenin expression and creatine kinase activity. The inhibition of the differentiation was regulated by apoptosis as determined by the detection of poly(ADP-ribose) polymerase (PARP) cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells when JNK activities were inhibited. Apoptosis was accompanied by marked expression and activation of c-Jun and p53 transcription factors. Taken together, our results indicate that basal JNK activities are essential for regulating skeletal muscle differentiation, and inhibition of JNK activation affects myogenesis by apoptosis dependent on c-Jun and p53 transcription factors.
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PMID:Involvement of c-Jun N-terminal kinase activities in skeletal muscle differentiation. 1575 Aug 49

After administration to normal mice, a subset of monoclonal (m) anti-DNA antibodies (Ab) derived from MRL-lpr/lpr mice was identified that enter cells, in vivo. In the kidneys, this was associated with glomerular hypercellularity and proteinuria. In cultured cells, the same mAb bound to myosin 1 on the cell surface, prior to internalization, nuclear localization and inhibition of apoptosis. The present study focuses on the mechanisms underlying the observed functional effects. Subcellular localization studies revealed that following internalization, a prototypic, nuclear localizing, m antibody (Ab; termed H7) co-localized with myosin 1, shortly after internalization, within caveolae, near the cell membrane. Cell fractionation studies confirmed the presence of both H7 and myosin within the caveolar fraction. Since variations in caveolin protein expression have been associated with apoptotic events in cancer cells, through p53 dependent and independent pathways, modulation of caveolin by intracellular H7 was evaluated. Cellular entry of the anti-DNA Ab resulted in an increase in caveolin protein expression. Furthermore, after exposure of cells to dexamethasone to induce apoptosis, the usual increase in p53 was inhibited in the presence of intracellular H7. Taken together, the results suggest that upregulation of caveolin and inhibition of p53 induction are involved in H7-induced, inhibition of apoptosis. Furthermore, they suggest that this inhibition contributes to the glomerular hypercellularity observed in normal mice with intranuclear H7. The results also raise the possibility that inhibition of apoptotic pathways during inflammation or/and autoimmunity could influence subsequent disease events. The novel mechanism of cellular perturbation is indirect and dependent on apoptotic stimuli, and it may account for the presence of intranuclear antibodies in inflammatory and normal tissues of individuals with lupus.
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PMID:Nuclear localizing anti-DNA antibodies enter cells via caveoli and modulate expression of caveolin and p53. 1582 7

Mitochondrial dysfunctions are frequently reported in cancer cells, but their direct involvement in tumorigenesis remains unclear. To understand this relation, we stimulated mitochondrial activity by overexpression of the mitochondrial triiodothyronine receptor (p43) in human dermal fibroblasts. In all clones, this stimulation induced morphologic changes and cell fusion in myotube-like structures associated with the expression of several muscle-specific genes (Myf5, desmin, connectin, myosin, AchRalpha). In addition, these clones displayed all the in vivo and in vitro features of cell transformation. This phenotype was related to an increase in c-Jun and c-Fos expression and extinction of tumor suppressor gene expression (p53, p21WAF1, Rb3). Lastly, reactive oxygen species (ROS) production was increased in positive correlation to the stimulation of mitochondrial activity. The direct involvement of mitochondrial activity in this cell behavior was studied by adding chloramphenicol, an inhibitor of mitochondrial protein synthesis, to the culture medium. This inhibition resulted in partial restoration of the normal phenotype, with the loss of the ability to fuse, a strong decrease in muscle-specific gene expression, and potent inhibition of the transformed phenotype. However, expression of tumor suppressor genes was not restored. Similar results were obtained by using N-acetylcysteine, an inhibitor of ROS production. These data indicate that stimulation of mitochondrial activity in human dermal fibroblasts induces cell transformation through events involving ROS production.
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PMID:Stimulation of mitochondrial activity by p43 overexpression induces human dermal fibroblast transformation. 1589 20

A 59-year-old man presented with a 10-cm x 8-cm tumoral plaque with a superficial nodule in the interscapular region of the back (Fig. 1). The lesion had been growing for 25 years. As a cystic lesion was suspected, the superficial nodule was biopsied. The histopathologic diagnosis was low-grade sarcoma with sclerosis. Two months after the initial biopsy, the lesion was completely excised, reaching the muscular fascia, with a 2-cm margin and with a free graft. Formalin-fixed paraffin-embedded samples were submitted to histologic and immunohistochemical study (4-microm paraffin sections); frozen tissue was submitted to electron microscopy. For histopathology, sections were stained with hematoxylin and eosin. Immunohistochemistry was performed following standard avidin-biotin immunoperoxidase procedures with primary antibodies for vimentin, CD34, smooth muscle-specific actin, bcl-2, S-100, desmin, myoglobin, factor VIII, p53 (all from DAKO, Copenhagen, Denmark), HHF-35 (Enzo Diagnostics, Farmingdale NY), cytokeratin (AE1/AE3) (Biogenex, San Ramon, CA), and factor XIIIa (Calbiochem Novabiochem Corporation, La Jolla, CA). At low magnification, the histologic study of the initial tumoral nodule revealed a poorly circumscribed mesenchymal proliferation, with fibroblastic-like neoplastic cells arranged in a fascicular and storiform pattern, admixed with extensive areas of sclerosis. At higher magnification, tumoral cells were spindle-shaped with hyperchromatic nuclei and scant cytoplasm. In some areas, sclerosis was so evident that a keloid-like pattern was seen (Fig. 2a). The surgical specimen showed a fibroblastic neoplastic proliferation infiltrating the dermis and hypodermis. In the dermis, cells were arranged in a storiform pattern, whereas in the hypodermis there was a honeycomb or lace-like pattern (Fig. 2b). There were also cellular areas alternating with sclerotic areas, with transitional zones in between, in both the dermis and hypodermis. The immunohistochemical study of the initial tumoral nodule and the surgical specimen showed that tumoral cells expressed vimentin, CD34 (Fig. 3), bcl-2, HHF-35, and smooth muscle actin. Neoplastic cells failed to show positivity with desmin, myoglobin, factor XIIIa, factor VIII, S-100, cytokeratin (AE1/AE3), and p53. An ultrastructural study revealed spindle cells having an irregular contour with a well-developed granular reticulum endoplasmic (REG) system in their cytoplasm, as well as some Golgi complexes and mitochondria. Also visible was the presence of many actin filaments and some myosin condensations (Fig. 4), characteristics of a fibroblastic cell with myofibroblastic differentiation. The final histopathologic diagnosis of the surgical specimen was sclerosing dermatofibrosarcoma protuberans. Two years after surgery, the patient is alive and well.
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PMID:Sclerosing dermatofibrosarcoma protuberans (DFSP): an unusual variant with focus on the histopathologic differential diagnosis. 1642 80

S100A4 (also known as Mts1, metastasin, p9Ka, pEL98, CAPL, calvasculin, Fsp-1, placental calcium-binding protein) belongs to the family of EF-hand calcium-binding proteins, whose expression is elevated in a number of pathological conditions. Although it is well documented that S100A4 is expressed in cancer cells and contributes to tumor cell motility and metastatic progression, the exact underlying mechanisms remain elusive. An important characteristic feature of S100 proteins is their dual function, inside and outside the cell. In this review, we focus on the intracellular function of S100A4. The review contains structural analysis of S1004 in comparison with other members of S100 proteins. Possible modes of the interaction of S100 proteins with targets are described. Several examples of best-studied molecular interactions involving S100A4 with heavy chain of nonmuscle myosin IIA, LAR-interacting protein liprin beta1 and tumor suppressor protein p53 are provided. We suggest that the binding of S100A4 to these molecules is critical for the S100A4 function. Further studies of the implications of these interactions in different molecular pathways may shed additional light on the role of S100A4 protein in the control of tumor cell motility and migration. We discuss the approaches for down-regulation of S100A4 expression and their potential for application in the clinics.
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PMID:Metastasis-associated protein S100A4: spotlight on its role in cell migration. 1750 19


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