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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of genetic abnormalities have been investigated in a variety of preleukaemic states RAS and FMS oncogene, p53 suppressor gene mutations and monoclonality in myelodysplastic syndromes (MDS), a paradigm for pre-leukemias have been observed. Other patients at risk of developing either secondary leukaemia or evolving into leukaemia have been similarly studied including haematologically normal patients in remission from lymphoma. Time from treatment to detection of genetic abnormalities is a significant factor in some of these patients which is consistent with the expansion of an abnormal clone. A case of non-dysplastic MDS has been identified with a 7q-karyotypic abnormality typical of therapy related MDS, abnormal progenitor growth and RAS mutations but with normal clinical features. Normal individuals have also been under investigation and found to have a low incidence of proto-oncogene mutations. A prospective study should enable us to determine if these parameters are indeed prognostic indicators.
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PMID:Genetic lesions in preleukemia. 824 36

We analysed p53 mutations in 24 patients with myelodysplastic syndrome (MDS) and overt acute myeloid leukaemia after a period of MDS, using polymerase chain reaction-single strand conformation polymorphism analysis. In exons 5 to 8, mobility shifts were detected in five of the 24 patients. Sequence analysis was subsequently performed, and four missense mutations (16.7%) and one silent nucleotide substitution were identified. Patients harbouring mutations were characterized as having advanced disease. Loss of the wild type allele was observed in three of the four patients with missense mutations. No mobility shifts of the N-ras or FMS gene were detected in these four patients. We next analysed the correlation of the p53 mutations with the progression of MDS in three patients. The mutation was accompanied by the progression in two of the three patients. These findings suggest that mutations of the p53 gene are associated with progression in some cases of MDS, while being compatible with stable disease or clonal evolution in others.
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PMID:Mutations of the p53 gene in myelodysplastic syndrome and overt leukemia. 855 5

For several decades, clinical and histologic assessment of various phenotypic properties has provided a basis for treatment planning. However, it is recognized that, preoperatively, clinical assessment identifies only 20% of patients with advanced disease. Furthermore, the variability in intraoperative sampling, the subjectivity and limitations of histologic interpretation, and the variability in response to standardized treatment modalities represent concerns associated with the current treatment of endometrial carcinoma. Presumably, early dissemination, early recurrence, treatment refractoriness and, ultimately, compromised survival are reflections of the inherent biologic characteristics of the tumor. A reasonable assumption is that proscribed molecular events determine various behavioral characteristics of tumors that become manifested at the time of transformation rather than evolving as the tumor volume increases. Therefore, the identification of one or more of these quantifiable molecular variables that directly or indirectly assess tumor biology would assist clinicians in determining patient risk status and in selecting treatment options. As noted, DNA ploidy is an independent, broadly applicable, quantifiable predictor of progression-free survival in patients with endometrial cancer and, therefore, warrants designation as a major prognostic factor or therapeutic determinant. Aneuploidy implies the presence of an abnormal quantity of genomic material and imparts a progressively less favorable prognosis as the DNA index increases. These assayable aberrancies of cellular DNA content presumably reflect the more extreme alterations at the molecular level. Because neoplastic transformation is generally a multistep process, aberrations in several proto-oncogenes or tumor suppressor genes (or both) presumably must be realized before a clinical malignancy develops. A number of genes that encode for various regulatory proteins are overexpressed in endometrial cancer. Whether these aberrancies are fundamental to the pathogenesis of this disease process is unclear. Nevertheless, there appears to be an association between DNA ploidy and the overexpression of several regulatory genes, such as c-fms, K-ras, HER-2/neu, and p53. Although overexpression of these oncogenes and tumor suppressor genes harbor prognostic significance in endometrial cancer, the ploidy status of the tumor appears to represent the most cogent objective variable. As the etiopathogenesis of endometrial carcinoma becomes more discernible, one can envision a limited number of tissue-specific molecular-genetic indices characterizing the risk status of patients. Because the estimated number of deaths from endometrial cancer has doubled since 1987, reassessing of the therapeutic determinants for this disease process is important. The management objective for endometrial cancer by the turn of the century should be the identification of patients at high risk for advanced disease or post-treatment recurrences (or both) at the time of clinical declaration of symptoms and diagnosis. Such pretreatment identification would afford patients at high risk for advanced or recurrent disease access to physicians with special expertise and would facilitate the evaluation and application of new or modified therapeutic modalities. Equally important would be the identification of patients at low risk for untoward outcome, thereby avoiding the cost and morbidity of excessive therapeutic measures.
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PMID:Endometrial neoplasia: prognostic significance of ploidy status. 886 93

Hodgkin's disease (HD) is characterized by the presence of the typical, clonal malignant Hodgkin and Reed-Sternberg (H-RS) cells in a hyperplastic background of normal reactive lymphocytes, plasma cells, histiocytes, neutrophils, eosinophils and stromal cells. The neoplastic nature of HD is based on aggressive clinical progression, presence of the proliferating and atypical H-RS cells, aneuploidy and cellular clonality. Immunophenotypical studies have demonstrated frequent expression of lymphoid "activation markers' including CD15, CD25, CD30, CD40, CD54, CD70, CD71, CD80, CD86 and MHC class II and less frequent expression of T- or B-cell-associated antigens by the neoplastic H-RS cells. The clonality of H-RS cells is demonstrated by clonal EBV integration, clonal cytogenetic abnormalities including p53 mutations and clonal immunoglobulin rearrangements in some HD cases. There is involvement of diverse molecules with oncogenic potential, including presence of viruses (Epstein-Barr virus and human herpes virus-6) and/or oncogenes/tumour suppressor genes (bcl-2/bcl-x, p53/MDM-2, c-myc, c-fms, N-ras, lck). The histopathological presentation and characteristic clinical features of HD correlate with an unbalanced production of multiple cytokines and define HD as a tumour of cytokine-producing cells. The proportion of malignant H-RS cells to reactive cellular components and fibrosis is dependent on the production of particular cytokines and allows subtyping of HD cases. The combined use of immunohistochemical, biochemical and molecular techniques has thus allowed recognition that HD represents more than one clinico-pathological entity with different types of H-RS cells. The defined mechanism for the biological nature, origin and oncogenesis of H-RS cells remains not fully understood, but is susceptible to further analysis using modern technology.
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PMID:Pathophysiology of Hodgkin's disease: functional and molecular aspects. 892 38

The effect of the CSF-1 receptor, cFMS, on the phosphorylation of the retinoblastoma (RB) tumor suppressor protein and on the cell cycle and cell differentiation was analyzed in a cultured promyelocytic leukemia cell capable of induced myelomonocytic differentiation. A series of cFMS-transfected HL-60 sublines with progressively higher cell surface FMS expression was derived by flow cytometric cell sorting. Overexpression of FMS increased the duration of the cell cycle, prolonging all cell cycle phases especially S phase, which doubled. The increased cell cycle generation times occurred without any detectable changes in RB expression level or phosphorylation. For retinoic acid (RA)-induced myeloid differentiation, progressive overexpression of FMS caused a greater fraction of cells to differentiate and G1/0 arrest compared to wild-type cells after the same number of cell cycle generation times. FMS overexpression also progressively increased the relative amount of dephosphorylated RB protein induced, while reducing the total amount of RB protein. The inducer-originated and FMS-driven changes in RB hypophosphorylation were not effected through changes in p21/WAF1/CIP1 in this p53-negative cell. Similar effects on differentiation and G0 arrest occurred with 1,25-dihydroxy vitamin D3 (D3)-induced monocytic differentiation. FMS did not significantly affect myeloid differentiation induced by DMSO, which does not target steroid-thyroid hormone receptors like RA and D3. While differentiation is typically associated with hypophosphorylated RB in all these cases, the kinetics indicate that the FMS-induced changes in cell cycle and cell differentiation do not depend in a direct causal fashion on the interconversion between hyperphosphorylated and hypophosphorylated RB.
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PMID:FMS (CSF-1 receptor) prolongs cell cycle and promotes retinoic acid-induced hypophosphorylation of retinoblastoma protein, G1 arrest, and cell differentiation. 894 Feb 55

The recent advances in the understanding of the pathogenesis of ovarian cancer have been helpful in addressing issues in diagnosis, prognosis and management. The study of ovarian tumours by novel techniques such as immunohistochemistry, fluorescent in situ hybridisation, comparative genomic hybridisation, polymerase chain reaction and new tumour markers have aided the evaluation and application of new concepts into clinical practice. The correlation of novel surrogate tumour specific features with response to treatment and outcome in patients has defined prognostic factors which may allow the future design of tailored therapy based on a molecular profile of the tumour. These have also been used to design new approaches to therapy such as antibody targeting and gene therapy. The delineation of roles of c-erbB2, c-fms and other novel receptor kinases in the pathogenesis of ovarian cancer has led initially to the development of anti-c-erbB2 monoclonal antibody therapy. The discovery of BRCA1 and BRCA2 genes will have an impact in the diagnosis and the prevention of familial ovarian cancer. The important role played by recessive genes such as p53 in cancer has raised the possibility of restoration of gene function by gene therapy. Although the pathological diagnosis of ovarian cancer is still confirmed principally on morphological features, addition of newer investigations will increasingly be useful in addressing difficult diagnostic problems. The increasingly rapid pace of discovery of genes important in disease, makes it imperative that the evaluation of their contribution in the pathogenesis of ovarian cancer is undertaken swiftly, thus improving the overall management of patients and their outcome.
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PMID:Molecular approaches to diagnosis and management of ovarian cancer. 915 81

Expression of exogenous wt-p53 in different tumor cell lines can induce growth arrest, apoptosis, or differentiation. Several experimental works have highlighted the relevance of cellular context in the determination of p53-mediated final outcomes. We recently observed that these diverse wt-p53 effects can also be induced by overexpressing wt-p53 in a single cell type-the 32D myeloid progenitors-transformed with different activated oncogenes. Here we show that 32D cells transformed with two different oncogenes, v-src or c-fms [S301,F969], both belonging to the CSF-1 transduction pathway, respond to exogenous wt-p53 expression with the same final outcome-monocytic differentiation. This result is particularly significant since 32D cells do not spontaneously express the CSF-1 receptor, whereas they undergo granulocytic differentiation upon G-CSF stimulation. These data strongly support the idea that wt-p53 suppressing effects result from interactions between p53 activity and the signaling pathways activated in different transformed cells.
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PMID:Oncogenes belonging to the CSF-1 transduction pathway direct p53 tumor suppressor effects to monocytic differentiation in 32D cells. 924 15

The molecular mechanisms underlying the development and evolution of myelodysplastic syndrome (MDS) are largely unknown. The increasing number of blast cells in the bone marrow correlate with poor prognosis and risk of developing acute leukemia. Such progression is frequently associated with increasing chromosomal abnormalities and genetic mutations. A cohort of 75 MDS patients were investigated for RAS, FMS and p53 mutations, and these molecular findings were related to cytogenetics, clinical status, transformation to acute leukemia, prognostic scores and survival. A mutation incidence of 57% (43/75) was found, with 48% (36/75) RAS mutations, 12% (9/75) FMS mutations and 8% (4/50) p53 mutations. The mutation status for RAS and FMS was related to MDS subgroup, increasing with poor-risk disease. The highest incidence was in the chronic myelomonocytic leukemia (CMML) subgroup. The most frequent RAS mutations were of codon 12 and a predominance of FMS codon 969 mutations was observed. A statistically significant increased frequency of transformation to AML was observed in MDS patients harboring RAS or FMS mutations (P < 0.02). Patients with oncogene mutations had a significantly poorer survival compared with those without mutations at 2 years and at the end of the period of follow-up (P < 0.02). Multivariate analysis including mutation, age, gender, diagnosis (FAB), cytogenetics and International score shows that the International score and mutation and age is the best predictive model of a poor outcome, (P < 0.0001). When the analysis was undertaken without the International score, mutation and gender was the best predictor of poor survival (P = 0.005). This study shows that oncogene mutation, indicative of genetic instability, is associated with disease progression and poor survival in MDS.
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PMID:RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. 963 16

The CSF-1 receptor (CSF-1R) is expressed in >50% of human breast cancers. To investigate the consequence of CSF-1R expression, hormone-dependent human breast cancer cell lines, MCF-7 and T-47D, were transfected with CSF-1R. Unexpectedly, CSF-1 substantially inhibited estradiol (E2) and insulin-dependent proliferation of MCF-7 transfectants (MCF-7fms) and prevented cyclin E/cdk2 and cyclin A/cdk2 activation, consistent with a G1 arrest. In contrast, CSF-1 increased DNA synthesis in T-47D transfectants (T-47Dfms) alone and with E2 or insulin. In response to CSF-1, there was a marked and sustained upregulation of the cyclin-dependent kinase inhibitor, p21Waf1/Cip1, in MCF-7fms but not T-47Dfms. CSF-1 also markedly upregulated cyclin D1 in MCF-7fms. The coordinate increase in cyclin D1 and p21 had the effect of decreasing the specific but not absolute activity of cyclin D1/cdk4. p53 was not involved since CSF-1 induction of p21 was unaffected by dominant-negative p53 expression. ERK activation by CSF-1 was robust and sustained in MCF-7fms and to a much lesser extent in T-47Dfms. Using pharmacological and transient transfection approaches, we showed that ERK activation was necessary and sufficient for p21 induction in MCF-7fms. Moreover, activated MEK inhibited E2-stimulated cdk2 activity. Our findings indicate that the consequence of CSF-1R-mediated signals in human breast cancer cells is dependent on the genetic background of the particular tumor.
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PMID:CSF-1 activates MAPK-dependent and p53-independent pathways to induce growth arrest of hormone-dependent human breast cancer cells. 1060 7

The aim of this study was to study the protein expression of six proto-oncogenes (epidermal growth factor receptor (EGFR), c-fms, c-myc, c-kit, c-erbB-2 and pan-ras) and one tumour suppressor gene (TP53), by immunohistochemical staining of normal cervical stratified squamous epithelium and cervical intra-epithelial neoplasia (CIN). Paraffin sections of 45 normal cervical specimens, 38 CIN grade one (CIN1), 37 CIN2 and 43 CIN3 were studied. An immunohistochemical (IHC) score was derived from the intensity of staining and the percentages of cells stained. In normal cervical specimens, a higher IHC score was found with EGFR and c-fms in superficial (S), intermediate (I) and parabasal (PB) cells compared with basal cells. In contrast, a higher IHC score was found with c-erbB-2 in basal cells in normal cervical specimens. Dysplastic cells in CIN had a higher IHC score with c-myc and c-erbB-2 than normal S/I and PB cells. Dysplastic cells had a higher score with EGFR than normal basal cells. However, a higher IHC score with EGFR and c-fms was found in normal S/I cells than dysplastic cells. These findings suggested that EGFR and c-fms were activated in more differentiated normal cells but were less active in less differentiated normal basal cells. However, EGFR was reactivated in dysplastic cells. Meanwhile, c-erbB-2 was activated in less differentiated normal basal cells and dysplastic cells, and was less active in differentiated normal cells. c-myc was activated in dysplastic cells. c-fms was more active in more differentiated normal cells and was not activated in less differentiated or dysplastic cells. c-kit, pan-ras and TP53 were not activated in normal nor dysplastic cervical cells. These results suggest EGFR, c-erbB-2 and c-myc may be important proto-oncogenes in CIN and that antibodies or anti-genes targeted against them may alter the progress of CIN to invasive cancer.
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PMID:Proto-oncogenes and p53 protein expression in normal cervical stratified squamous epithelium and cervical intra-epithelial neoplasia. 1067 85


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