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)

We have investigated the mechanism by which the simian virus 40 large T antigen (SVLT) interferes with the differentiation of C2 myoblasts. SVLT mutants, defective either in the Rb binding site, near the N-terminal end, in a region that affects binding to p53, or in the nuclear transport signal, were also employed to determine whether the interference was especially dependent on these functional domains. It was found that wild-type (wt) SVLT strongly inhibited the terminal differentiation of mouse C2 myoblasts, but this arrest occurred only after the synthesis of myogenin, an initial step in biochemical differentiation. Neither the synthesis nor some basic activities of MyoD appeared to be affected by wt SVLT. In these transformants, mitogen depletion elicited an increase in the Rb level comparable to that in normal C2 cells; wt SVLT, however, promoted the phosphorylation of a large part of the induced Rb. Mutations affecting nuclear transport were far more critical for the ability to interfere with myogenic differentiation than were those affecting the transforming potential; cytoplasmic SVLT expression was fully compatible with the terminal differentiation of C2 cells, despite enabling them to grow in semisolid medium, thus showing that the myogenesis-inhibiting property can be dissociated from transforming competence. The remaining SVLT mutants presented different degrees of ability to inhibit differentiation (as shown by the expression of tissue-specific markers in transformants). The inhibiting mutants, including the Rb binding site mutant, were able to promote a higher state of Rb phosphorylation than that observed in either normal cells or cytoplasmic-SVLT transformants.
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PMID:The inhibition of cultured myoblast differentiation by the simian virus 40 large T antigen occurs after myogenin expression and Rb up-regulation and is not exerted by transformation-competent cytoplasmic mutants. 747 13

Terminal differentiation is coupled to withdrawal from the cell cycle. The cyclin-dependent kinase inhibitor (CKI) p21Cip1 is transcriptionally regulated by p53 and can induce growth arrest. CKIs are therefore potential mediators of developmental control of cell proliferation. The expression pattern of mouse p21 correlated with terminal differentiation of multiple cell lineages including skeletal muscle, cartilage, skin, and nasal epithelium in a p53-independent manner. Although the muscle-specific transcription factor MyoD is sufficient to activate p21 expression in 10T1/2 cells, p21 was expressed in myogenic cells of mice lacking the genes encoding MyoD and myogenin, demonstrating that p21 expression does not require these transcription factors. The p21 protein may function during development as an inducible growth inhibitor that contributes to cell cycle exit and differentiation.
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PMID:p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. 786 39

p202 is a primarily nuclear, interferon-inducible murine protein that is encoded by the Ifi 202 gene. Overexpression of p202 in transfected cells retards cell proliferation. p202 modulates the pattern of gene expression by inhibiting the activity of various transcription factors including NF-kappaB, c-Fos, c-Jun, E2F-1, and p53. Here we report that p202 was constitutively expressed in mouse skeletal muscle and that the levels of 202 RNA and p202 greatly increased during the differentiation of cultured C2C12 myoblasts to myotubes. When overexpressed in transfected myoblasts, p202 inhibited the expression of one muscle protein (MyoD) without affecting the expression of a second one (myogenin). Thus, the decrease in the level of MyoD (but not of myogenin) during muscle differentiation may be the consequence of the increase in p202 level. Overexpressed p202 also inhibited the transcriptional activity of both MyoD and myogenin. This inhibition was correlated with an interaction of p202 with both proteins, as well as the inhibition by p202 of the sequence-specific binding of both proteins to DNA. This inhibition of the expression of MyoD and of the transcriptional activity of MyoD and myogenin may account for the inhibition of the induction of myoblast differentiation by premature overexpression of p202.
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PMID:Increase in p202 expression during skeletal muscle differentiation: inhibition of MyoD protein expression and activity by p202. 944 5

Muscle growth results from a set of complex processes including myogenic transcription factor's expression and activity, cell cycle withdrawal, myoblast fusion in myotubes, and acquisition of an apoptosis-resistant phenotype. Myostatin, a member of the TGFbeta family, described as a strong regulator of myogenesis in vivo Nature 387 (1997), 83; FEBS Lett. 474 (2000), 71 is upregulated during in vitro differentiation Biochem. Biophys. Res. Commun. 280 (2001), 561. To improve characterization of myostatin's myogenic influence, we stably transfected vectors expressing myostatin and myostatin antisense in C2C12 myoblasts. Here, we found that myostatin inhibits cell proliferation and differentiation. Our results also indicate that myogenin is an important target of myostatin. In addition, overexpressed but not endogenous myostatin decreases MyoD protein levels and induces changes in its phosphorylation pattern. We also established that myostatin overexpression reduces the frequency of G0/G1-arrested cells during differentiation. Conversely, inhibition of myostatin synthesis leads to enhanced cell cycle withdrawal and consequently stimulates myoblast differentiation. We examined the expression patterns of the pRb, E2F1, p53, and p21 proteins involved in cell cycle withdrawal. We found that myostatin overexpression increases p21 and p53 expression, as it does accumulation of hypophosphorylated Rb. Interestingly, myostatin overexpression strongly reduced low-mitogen-induced apoptosis, whereas antisense expression induced contrary changes. In conclusion, these data show the influence of overexpressed myostatin on myoblast proliferation, differentiation, and apoptosis is extended to endogenous myostatin. Though some differences in overexpression or inhibition of endogenous myostatin were observed, it appears that myogenin and p21 are essential targets of this growth factor.
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PMID:Mechanisms involved in the inhibition of myoblast proliferation and differentiation by myostatin. 1274 55

In the literature, sufficient attention has not been paid to the precise subcellular localization of immunohistochemical signals, the knowledge of which is essential for proper interpretation of immunostains and distinction of genuine staining from biotin-associated or other nonspecific stainings. The subcellular localization of the signals can in fact be easily deduced from the known biologic or ultrastructural characteristics of the antigens. Extracellular antigens obviously are located in the extracellular compartment. Cellular antigens fall into 3 major groups: membranous, nuclear, and cytoplasmic. Membranous antigens include cell adhesion molecules (such as E-cadherin, N-CAM), cell surface/transmembrane receptors and proteins (such as tyrosine kinase receptors, most leukocyte antigens, CD10, CEA), and molecules linking surface molecules to cytoskeleton (such as beta-catenin, dystrophin). Nuclear antigens include cell cycle-associated proteins (such as cyclins, p16, Ki-67), nuclear enzymes (such as TdT), transcription factors (such as TTF-1, CDX-2, myogenin, PAX-5), tumor suppressor gene products (such as p53, p63, WT1, Rb), steroid hormone receptors (such as ER, PR), calcium-binding proteins (such as S-100 protein, calretinin), and some viral proteins (such as CMV, herpes). Cytoplasmic antigens can take up a granular pattern due to localization in organelles, granules, or secretory vesicles (such as chromogranin, hormones, lysozyme, HMB-45), fibrillary pattern attributable to the filamentous nature of the molecules (intermediate filaments and microfilaments), or diffuse or patchy pattern due to localization in the cytosol or large vesicles (such as myoglobin, albumin, thyroglobulin). Aberrant localization of the molecules, when present, can provide important insight into disease processes and aid in their diagnosis, such as loss of membranous E-cadherin expression in lobular breast carcinoma, aberrant nuclear localization of beta-catenin in colorectal adenocarcinoma, pattern of ALK staining in anaplastic large cell lymphoma correlating with the different types of chromosomal translocations, presence of additional cytoplasmic CD10 staining in the enterocytes indicative of microvillous inclusion disease, and "reversed" staining for EMA in micropapillary mammary carcinoma.
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PMID:Subcellular localization of immunohistochemical signals: knowledge of the ultrastructural or biologic features of the antigens helps predict the signal localization and proper interpretation of immunostains. 1530 32

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

PW1 is a mediator of p53 and TNFalpha signaling pathways previously identified in a screen to isolate muscle stem cell regulators. We generated transgenic mice carrying a C-terminal deleted form of PW1 (DeltaPW1) which blocks p53-mediated cell death and TNFalpha-mediated NFkappaB activation fused to the myogenin promoter. Embryonic/fetal muscle development appears normal during transgene expression, however, postnatal transgenic pups display severe phenotypes including runtism, reduced muscle mass and fiber diameters resembling atrophy. Atrogin-1, a marker of skeletal muscle atrophy, is expressed postnatally in transgenic mice. Electron microscopic analyses of transgenic muscle reveal a marked decrease in quiescent muscle satellite cells suggesting a deregulation of postnatal stem cells. Furthermore, transgenic primary myoblasts show a resistance to the effects of TNFalpha upon differentiation. Taken together, our data support a role for PW1 and related stress pathways in mediating skeletal muscle stem cell behavior which in turn is critical for postnatal muscle growth and homeostasis. In addition, these data reveal that postnatal stem cell behavior is likely specified during early muscle development.
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PMID:Embryonic deregulation of muscle stress signaling pathways leads to altered postnatal stem cell behavior and a failure in postnatal muscle growth. 1589 71

The discovery of two new p53 homologs, p73 and p63, has defined a family of transcription factors heavily involved in the control of growth suppression, apoptosis, differentiation and development. While p53-deficient mice undergo spontaneous tumors, p73 and p63 knockout mice exhibit severe developmental defects. We demonstrate here that p73 gene is an in vivo transcriptional target of the muscle regulatory factors MyoD, myogenin, Myf5 and Myf6. Ectopic expression of the transcriptional repressor deltaEF1/ZEB/zfhx1a counteracts MyoD/Myf5- or MyoD/Myf6-mediated transcriptional activation of p73. A distinct pattern of in vivo recruitment of muscle regulatory factors and deltaEF1 on p73 regulatory regions was found between proliferating and differentiating muscle cells. We also found that deltaEF1 plays a role in the transcriptional regulation of p53 family members during keratinocytic differentiation. Mouse embryo fibroblasts derived from deltaEF1-deficient mice exhibit unbalanced expression of DeltaNp63, TAp73 and DeltaNp73 but not of TAp63 and p53. The analysis of tissues derived from deltaEF1+/- mice exhibit a selective enrichment of DeltaNp63 in skin.
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PMID:deltaEF1 repressor controls selectively p53 family members during differentiation. 1600 24

Embryonal sarcoma of the liver is a rare, aggressive malignant tumor that typically occurs in children and teenagers. Microscopic features include spindle, oval, or stellate cells with poorly defined cell borders, nuclear pleomorphism and multinucleation, and variable immunoreactivity to cytokeratin, vimentin, and alpha-1-antitrypsin. Intracellular and extracellular PAS-positive, diastase-resistant hyaline globules are commonly present. The authors evaluated a panel of IHC stains to better define the pattern of immunoreactivity in this tumor. Embryonal sarcomas of the liver were identified from archival files and were immunostained with antibodies: cytokeratin AE1/3, hepatocyte, SMMS, myogenin, calponin, h-caldesmon, desmin, S100, vimentin, CD34, C-kit (CD117), CD10, ALK-1, PE10, Bcl2, p53, and Ki-67. Six cases were identified. Patient age ranged from 6 to 24 years. Tumors ranged from 10 to 20 cm and contained spindled and epithelioid areas with PAS-positive, diastase-resistant globules and atypical cells with focal multinucleation. All cases showed immunoreactivity with vimentin and five showed immunoreactivity with Bcl2. Focal immunoreactivity was seen with cytokeratin AE1/3 in three cases, CD10 in four, calponin in two, desmin in one, and p53 in four. All tumors were negative with hepatocyte, myogenin, CD34, SMMS, h-caldesmon, PE10, ALK-1, and S100. No cytoplasmic staining was seen with C-kit. The proliferation index ranged from 30% to 95%. The diagnosis of embryonal sarcoma is based on typical morphologic features in a large liver tumor occurring in a young patient. The most useful IHC stains help to exclude tumors such as hepatoblastoma, hepatocellular carcinoma, embryonal rhabdomyosarcoma, and other sarcomas.
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PMID:Immunohistochemical analysis of embryonal sarcoma of the liver. 1678 89

Initially identified as a group of auxiliary protein factors involved in transcriptional regulation by steroid hormone receptors as well as by other members of the nuclear receptor superfamily, the steroid receptor coactivators (SRCs) have since then been implicated in the transcriptional regulation of other transcription factors which are important components of very different signaling pathways. Members of the SRC family have been shown to interact with myogenin, MEF-2, transcriptional enhancer factor (TEF), NF-kappaB, AP-1, STAT, p53, and E2F1, suggesting that SRC coactivators participate in diverse cellular processes. Recent evidence indicates that various post-translational modifications play critical roles in determining the final transcriptional output and specificity of SRC coactivators. In this review, we summarized the current knowledge concerning post-translational modifications, dynamic interplay between different modifications, and patho-physiological relevance of the modifications of SRC proteins.
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PMID:Regulation of SRC family coactivators by post-translational modifications. 1736 49


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