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)

p27kip1 and p21cip1 are cyclin-dependent kinase (cdk) inhibitors which along with p53 play critical roles in the control of cell cycle progression. Accumulation of p27kip1 in post-mitotic neurons is a major event of neurogenesis. We hypothesized that a dysregulation of the expression of p53 and these cdk inhibitors underlies cellular proliferation in medulloblastomas, and tested this hypothesis by investigating p27kip1, p21cip1, Bcl2 and p53 immunoreactivity in 14 medulloblastoma tumors. We noted an inverse relationship between p27kip1 expression and cellular proliferation (MIB1). Focal islands of neuroblastic or glial differentiation expressed high levels of p27kip1, while the undifferentiated, highly-proliferative population of tumor cells showed no detectable p27kip1 expression, thus suggesting a role for p27kip1 in cell cycle control in medulloblastoma. In addition, there was no detectable p21cip1 expression in any of the medulloblastomas studied. The low level of apoptosis displayed by these tumors was not associated with the expression of Bcl-2. A significant relationship was found between detection of p53 protein and poor survival. Since, p21cip1 and p27kip1 are often co-expressed with other INK4 family of cdk inhibitors during the induction of cellular differentiation and are synergistic in their effect, a deregulation of their coordinate expression may underlie the lack of complete differentiation in medulloblastoma.
 ...
PMID:Expression of p27kip1 and p53 in medulloblastoma: relationship with cell proliferation and survival. 1078 68

Medulloblastomas are among the most common malignancies in childhood, and they are associated with substantial mortality and morbidity. The molecular pathogenesis as well as the ontogeny of these neoplasms is still poorly understood. We have generated a mouse model for medulloblastoma by Cre-LoxP-mediated inactivation of Rb and p53 tumor suppressor genes in the cerebellar external granular layer (EGL) cells. GFAP-Cre-mediated recombination was found both in astrocytes and in immature precursor cells of the EGL in the developing cerebellum. GFAP-Cre;Rb(LoxP/LoxP);p53(-/- or LoxP/LoxP) mice developed highly aggressive embryonal tumors of the cerebellum with typical features of medulloblastoma. These tumors were identified as early as 7 weeks of age on the outer surface of the molecular layer, corresponding to the location of the EGL cells during development. Our results demonstrate that loss of function of RB is essential for medulloblastoma development in the mouse and strongly support the hypothesis that medulloblastomas arise from multipotent precursor cells located in the EGL.
 ...
PMID:Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. 1078 70

Medulloblastoma, a malignant invasive tumor of the cerebellum, is one of the most common neoplasms of the nervous system in children. Utilization of the human neurotropic virus JC virus (JCV) early gene T-antigen allowed the development of a transgenic animal that models human medulloblastoma. Here we describe the characterization of two distinct populations of cells derived from the JCV-induced mouse medulloblastoma. Results from immunohistochemical and biochemical studies revealed the expression of T-antigen in some but not all tumor cells. In T-antigen-producing cells, T-antigen was found in association with wild-type p53 and pRb, two tumor suppressors that control cell growth and differentiation. In cells that lack expression of T-antigen, a novel mutant p53 with a deletion between residues 35 and 123 was detected. Morphological differences were observed between the two populations of cells, though there was no significant difference in their growth rates. However, subcutaneous transplantation of the T-antigen-positive, but not T-antigen-negative, cells resulted in the development of massive tumors in experimental animals. In light of earlier reports on the association of JCV with human medulloblastoma, the mouse cell lines described in this study may provide a valuable tool for deciphering the pathways involved in the formation and progression of medulloblastoma.
 ...
PMID:Identification of a novel p53 mutation in JCV-induced mouse medulloblastoma. 1093 89

The large cell (LC) subtype is a recently described histologic variant of medulloblastoma (Mb) associated with a rapid and aggressive clinical course. We describe the genomic profile of a LC-Mb tumor obtained from a patient who developed recurrent and fulminant disease despite 'good-risk' features at diagnosis and state- of-the-art multidisciplinary therapy. The tumor sample was analyzed using comparative genomic hybridization (CGH) and complementary molecular approaches. CGH revealed amplicons at chromosome bands 2p24-25, 2q12-22, and 17p11; losses of chromosomes 11q and 18; and low-level gains of 3q, 11p, 13q and 14q. Southern blot analysis confirmed N-myc amplification. No evidence of p53 mutation was detected. The genomic profile of this LC-Mb tumor sample revealed a distinctive pattern of genetic alterations including amplification of N-myc and anonymous oncogenes at chromosome bands 2q12-22 and 17p11. These genomic abnormalities are uncommon in other subtypes of Mb.
 ...
PMID:Multiple genomic alterations including N-myc amplification in a primary large cell medulloblastoma. 1094 Jul 69

Medulloblastoma accounts for 20 to 25% of all intracranial neoplasms in children. The significance of the presence of isochromosome 17q (i(17q)), proliferative potential, apoptotic activity, and expression of c-erbB-2, bd-2, and p53 proteins in predicting long-term survival of patients with medulloblastomas was investigated. Twenty children were divided into two groups (favorable and poor outcome groups). Ten children with favorable outcome (FO) were disease-free during the follow-up period (median: 61.5 months). The other ten children with poor outcome (PO) died of disease progression, having a median survival of 18 months. Fluorescent in situ hybridization (FISH) for i(17q), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), and immunohistochemistry for Ki-67, c-erbB-2, bcl-2, and p53 proteins was performed in these patients. Nine out of 17 children showed i(17q). There was no difference in the rate of positive i(17q) between the FO and PO groups. The presence of i(17q) was not significantly related to biological factors that we investigated. Unlike the prominent presence of the proliferative potential and p53 expression in children with PO, apoptotic activity and expression of c-erbB-2 and bcl-2 had no correlation with the outcome.
 ...
PMID:The effect of isochromosome 17q presence, proliferative and apoptotic indices, expression of c-erbB-2, bcl-2 and p53 proteins on the prognosis of medulloblastoma. 1098 96

Brain malignancies represent the most common solid tumors in children, and they are responsible for significant mortality and morbidity. The molecular basis of the most common malignant pediatric brain tumor, medulloblastoma, is poorly understood. Mutations in several genes including the human homologue of the Drosophila segment polarity gene, patched (PTCH), the adenomatous polyposis coli gene (APC), beta-catenin, and p53 have been reported in subsets of hereditary and sporadic medulloblastoma. Inactivation of one Ptc allele in mice results in a 14% incidence of medulloblastoma. Here, we report a dramatic increase in the incidence (>95%) and accelerated development (prior to 12 weeks of age) of medulloblastoma in mice heterozygous for Ptc that lack p53. The acceleration of tumorigenesis in Ptc+/- mice is specific for loss of p53, because no change in tumor incidence was observed in Ptc+/- mice carrying a mutation in APC (Min+/-) or in Ptc+/- mice deficient in p19ARF. Thus, there is a specific interaction between p53 loss and heterozygosity of Ptc that results in medulloblastoma. This may be a consequence of increased genomic instability associated with loss of p53 function that may enhance the rate of acquisition of secondary mutations. Ptc+/- p53-/- mice provide a useful model for investigation of the molecular bases of medulloblastoma and for evaluation of the efficacy of therapeutic intervention strategies in a spontaneously arising endogenous brain tumor.
 ...
PMID:Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. 1121 43

The clinical, histopathological, and ultrastructural features of a cerebellar liponeurocytoma are reported. The tumor, a 3-cm mass localized in the right cerebellar hemisphere, was resected from a 61-year-old man clinically presenting with symptoms of intracranial hypertension. The lesion was composed of small, in some areas closely packed, medulloblastoma-like cells with prominent areas of lipidization phenomena. Moreover, mitoses, cellular atypia, and numerous vascular structures were focally observed. Glial and neuronal differentiation was immunohistochemically noted (glial fibrillary acidic protein, synaptophysin, neurofilaments, and neuron-specific enolase positivity). The p53 oncoprotein was detected in the majority of neoplastic cells and a moderate proliferation activity, evaluated by Mib-1 antibody, was focally appreciated. Ultrastructural study did not show evident neuritic processes, synapses, or dense core neuroendocrine granules. This cerebellar tumor previously called lipidized medulloblastoma and recently renamed cerebellar liponeurocytoma is considered an adult neoplasm with excellent prognosis histologically presenting prominent lipidized areas and, at the immunohistochemical and ultrastructural level, both glial and neuronal differentiation. The present study provides the first description of a less differentiated and histologically more aggressive form of this unusual tumor.
 ...
PMID:Cerebellar liponeurocytoma: immunohistochemical and ultrastructural study of a case. 1129 21

To improve the survival rate, gene therapy, such as the replacement of inactivated tumor suppressor genes, has become a new investigational adjuvant treatment modality for human malignancies. We investigated the effect of adenovirus(Ad)-mediated transfer of wildtype p53 tumor suppressor gene on the medulloblastoma cell line, Daoy, which harbors mutant-type p53 gene. At 50 multiplicity of infection (moi), immunohistochemical staining with p53 monoclonal antibody showed positive staining in all cells 2 days after Ad-CMV-p53 infection. The high expression of wild-type p53 protein was detected in Ad-CMV-p53-infected cells, and expression of wild-type p53 protein peaked on day 2 after the infection. The growth of Ad-CMV-p53-infected cells was greatly suppressed in vitro, and the Ad-CMV-p53 treatment significantly reduced the tumor mass in vivo. The mean weight of Ad-CMV- infected tumors was only 16% of those which were mock infected, and 25% of those which were Ad-CMV-beta-gal infected. On microscopic examination, Ad-CMV-p53-infected tumors showed numerous apoptotic bodies. This Ad-CMV-p53 gene transfer showed high transduction efficacy and expression, resulting in significant growth inhibition of Daoy harboring mutant type p53.
 ...
PMID:Growth-inhibitory effect of adenovirus-mediated p53 gene transfer on medulloblastoma cell line, Daoy, harboring mutant p53. 1130 65

Nodular/desmoplastic medulloblastomas are a well-established histopathological subtype containing reticulin-free nodules or "pale islands' that are comprised of cells with round "neurocytic" nuclei and abundant cytoplasm. Significant neuronal maturation occurs within nodules. We used immunohistochemistry to evaluate neuronal differentiation in the nodules of 6 of these tumors. The neuronal markers NeuN, synaptophysin, and MAP-2 were identified in the "pale islands" of all 6 nodular medulloblastomas examined, and high and medium molecular weight nonphosphorylated neurofilaments were detected in 2 of the 6 cases. We also observed collections of apoptotic cells within nodules. Given the known role of neurotrophin signaling in neuronal maturation and apoptosis, we analyzed immunohistochemically the distribution of neurotrophin receptors TrkA and TrkC and their primary ligands NGF and NT3 in 14 nodular medulloblastomas. TrkA and TrkC were detected in 13 and 10 cases, respectively, and were predominantly localized within nodules. NGF and NT3 were distributed diffusely with some nodular accentuation. The localized expression of Trk receptors within nodules of desmoplastic medulloblastomas suggests neurotrophin signaling is involved in the apoptosis and neuronal differentiation in medulloblastomas. We also examined expression of p53 and BCL-2 in these tumors; both were prominent in internodular regions but only weakly expressed within nodules. Trk receptors, p53, and BCL-2 are all expressed during development of the normal cerebellum. Interestingly, the immunohistochemical expression profile of these proteins in the differentiating nodules of medulloblastomas is in many ways similar to their expression in the developing cerebellum. Thus similar signaling pathways may be operational in cerebellar development and medulloblastoma tumor differentiation.
 ...
PMID:Apoptosis, neuronal maturation, and neurotrophin expression within medulloblastoma nodules. 1137 21

JC virus (JCV) together with Simian virus 40 (SV40) and BK virus (BKV), belong to the polyomavirus group and these viruses are neuro-oncogenic to rodents by expression of large T antigen (LT), which binds to cellular p53 and pRB thus reducing the anticancer potential of the cell. The function of LT has not been clarified because small t antigen (st) is transcribed from the same start codon as the overlapping reading frame of LT, and is translated as a different protein with the same N-terminal residues (1-81 amino acids) by a splice-site variant of mRNA. To elucidate the function of LT without st, we constructed plasmids that express LT only by deleting the splicing region including the C-terminus of st, and consequently stable cell lines were established that express only JCLT, SV40LT and BKLT. The growth rates of these cells were examined in colonies on soft agar and it was found that LT alone has a transforming capacity; the order of efficiency being SV40LT, BKLT and JCLT. In addition, to verify the involvement of JCV in human medulloblastoma, eight cases of medulloblastoma, six cases of frozen material and five cases of paraffin-embedded tissues which included three cases of frozen tissues, were examined. PCR assay, genomic Southern blotting, and in situ hybridization were applied to detect the JCV genome, and LT and st were examined by immunohistochemistry; the results were compared with JCV-infected tissues as a positive control. All methods failed to detect not only JCV genome but also LT protein in medulloblastoma and it was concluded that JCV LT has transforming activities in rodent cells, but is not related to human medulloblastoma.
 ...
PMID:JC virus large T protein transforms rodent cells but is not involved in human medulloblastoma. 1139 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>