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)

Although pituitary tumors arise as benign monoclonal neoplasms, genetic alterations have not readily been identified in these adenomas. We studied restriction fragment abnormalities involving the GH gene locus, and mutations in the p53 and H-, K- and N-ras genes in 22 human GH cell adenomas. Twenty two nonsecretory adenomas were also examined for p53 and ras gene mutations. Seven prolactinoma DNA samples were tested for deletions in the multiple endocrine neoplasia-1 (MEN-1) locus, as well as for rearrangements in the hst gene, a member of the fibroblast growth factor family. Pituitary adenoma tissue and lymphocytes were obtained from patients at the time of transsphenoidal surgery. In DNA from GH-cell adenomas, identical GH restriction patterns were detected in both pituitary and lymphocyte DNA in all patients and in one patient with a mixed GH-TSH cell adenoma. Using polymerase chain reaction (PCR)-single stranded conformation polymorphism analysis, no mutations were detected in exons 5, 6, 7, and 8 of the p53 gene in GH cell adenomas nor in 22 nonsecretory adenomas. Codons 12/13 and 61 of H-ras, K-ras, and N-ras genes were also intact in GH cell adenomas and in nonsecretory adenomas. Site-specific probes for chromosome 11q13 including PYGM, D11S146, and INT2 were used in 7 sporadic PRL-secreting adenomas to detect deletions of the MEN-1 locus on chromosome 11. One patient was identified with a loss of 11p, and the remaining 6 patients did not demonstrate loss of heterozygosity in the pituitary 11q13 locus, compared to lymphocyte DNA. None of these patients, demonstrated hst gene rearrangements which also maps to this locus. These results show that p53 and ras gene mutations are not common events in the pathogenesis of acromegaly and nonsecretory tumors. Although hst gene rearrangements and deletions of 11q13 are not associated with sporadic PRL-cell adenoma formation, a single patient was detected with a partial loss of chromosome 11, including the putative MEN-1 site.
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PMID:Molecular screening of pituitary adenomas for gene mutations and rearrangements. 810 Aug 31

Loss of cell cycle control and the inability of the cell to repair DNA at cell cycle checkpoints results in the propagation of genetic lesions which ultimately leads to cancer. To further our understanding of these pathways in pituitary tumorigenesis, we have investigated the effects of DNA damage by gamma radiation in a murine pituitary adenoma (AtT20) cell line with attention to cell cycle checkpoint responses, the induction of apoptosis, and the expression of known regulators of these processes. Irradiated cells exhibited characteristic morphologic changes of apoptosis beginning at 24 h, which included cell shrinkage, chromatin condensation, and cytoplasmic vacuolization, yet the ability to exclude trypan blue was retained for several days. DNA fragmentation could be demonstrated by ethidium bromide staining beginning at 24 h post-irradiation. By propidium iodide staining and flow cytometry, irradiated cells demonstrated G1 and G2 arrest at 24 h, followed at 48 h by a shift to a sub-G1 position of the apoptotic cell population. The G1 arrest coincided with an induction of p53 protein by Western blot analysis which peaked at 4 h post-radiation and persisted beyond 48 h. Expression of c-myc in irradiated cells was found to progressively decrease at 12, 24, and 48 h. Basal expression of the bcl-2 gene in AtT20 cells was found to be 15-fold higher than in normal mouse pituitary by RNase protection assay. Bcl-2 mRNA and protein levels, however, remained unchanged at 24 and 48 h following gamma-irradiation, suggesting that apoptosis occurs independently of bcl-2 gene expression in these cells following this stimulus, as reported in other cell types. We conclude that AtT20 cells undergo G1 and G2 arrest following DNA damage and that a significant proportion of cells then undergo apoptosis. The G1 arrest at 24 h is concurrent with a strong induction of p53 protein, while c-myc expression progressively diminishes. Bcl-2 is highly expressed in this cell line. The absence of variation in bcl-2 expression during apoptosis could be related to its high basal level in these cells.
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PMID:Molecular and cellular responses to DNA damage in a murine pituitary adenoma cell line. 879 54

We reported a case of sarcomatous transformation of pituitary adenoma occurring in a 21-year-old woman. She had previously undergone surgery for pituitary adenoma (prolactinoma) 5 years earlier. Since then, she had received only bromocriptine medication therapy. The operation was repeated because of a relapse of the tumors. Histologically, the tumors were composed of adenomatous epithelial nests and fibrosarcomatous spindle cell components intermingled with each other. lmmunohistochemically, adenomatous epithelial cells were stained positively with cytokeratin and prolactin. Fibrosarcomatous spindle cells were stained only with vimentin. The proliferation activity (Ki-67 expression) was much higher in the sarcomatous components than in common pituitary adenoma. p53 immunostaining was also positive in sarcomatous components. This was thought to be the first reported case of sarcomatous transformation of pituitary adenoma not associated with radiation therapy.
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PMID:Sarcomatous transformation of pituitary adenoma after bromocriptine therapy. 949 Feb 82

Astrocytic tumors occasionally arise in the central nervous system following radiotherapy. It is not clear if these gliomas represent a unique molecular genetic subset. We identified nine cases in which an astrocytoma arose within ports of previous radiation therapy, with total doses ranging from 2400 to 5500 cGy. Irradiated primary lesions included craniopharyngioma, pituitary adenoma, Hodgkin's lymphoma, ependymoma, pineal neoplasm, rhabdomyosarcoma, and three cases of lymphoblastic malignancies. Patients ranged from 9 to 60 years of age and developed secondary tumors 5 to 23 years after radiotherapy. The 9 postradiation neoplasms presented as either anaplastic astrocytoma (3 cases) or glioblastoma multiforme (6 cases). Two of the latter contained malignant mesenchymal components. We performed DNA sequence analysis, differential polymerase chain reaction (PCR), and quantitative PCR on DNA from formalin-fixed, paraffin-embedded tumors to evaluate possible alterations of p53, PTEN, K-ras, EGFR, MTAP, and p16 (MTS1/CDKN2) genes. By quantitative PCR, we found EGFR gene amplification in 2 of 8 tumors. One of these demonstrated strong immunoreactivity for EGFR. Quantitative PCR showed chromosome 9p deletions including p16 tumor suppressor gene (2 of 7 tumors) and MTAP gene (3 of 7). Five of 9 tumors demonstrated diffuse nuclear immunoreactivity for p53 protein. Sequencing of the p53 gene in these 9 cases revealed a mutation in only one of these cases, a G-to-A substitution in codon 285 (exon 8). Somewhat unexpectedly, no mutations were identified in PTEN, a commonly altered tumor suppressor gene in de novo glioblastoma multiformes. Unlike some radiation-induced tumors, no activating point mutations of the K-ras proto-oncogene or base pair deletions of tumor suppressor genes were noted. These radiation-induced tumors are distinctive in their high histological grade at clinical presentation. The spectrum of molecular genetic alterations appears to be similar to that described in spontaneous high grade astrocytomas, especially those of the de novo type.
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PMID:Molecular genetic alterations in radiation-induced astrocytomas. 1032 96

A 38-year-old male presented with a cystic lesion at the foramen magnum due to intracranial dissemination from a pituitary adenoma. The primary tumor had required reoperation for regrowth twice. The tumor at the foramen magnum was removed surgically. Two smaller solid tumors were located in the left parietal convexity and the right temporal lobe. The former tumor was also removed surgically and the latter was observed. Histological examination showed the typical characteristics of pituitary adenoma in both surgical specimens. Immunohistochemical staining with MIB-1 and p53 antibodies showed low (< 1%) and negative reaction. Patients with pituitary adenoma, even benign tumors, must be carefully followed up for signs of metastasis.
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PMID:Cystic lesion at the foramen magnum disseminated from a pituitary adenoma--case report. 1048 40

In an attempt to understand the roles of the tumour suppressor gene p53 and the proto-oncogene bcl-2 in cell death and survival in pituitary adenomas, we investigated the relationship of their expression to the apoptotic response of two pituitary adenoma cell lines (GH3 and AtT-20) to bromocriptine. An MTT (3-4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrasolium bromide) assay was performed after treatment with bromocriptine for various periods of time over a range of concentrations to determine the effect of this drug on cell growth. Bromocriptine inhibited growth of GH3 and AtT-20 cells in a dose dependent manner. DNA fragmentation was assessed in GH3 and AtT-20 cells exposed to 10 ug/ml bromocriptine- for 48 h and 72 h. The DNA of GH3 and AtT-20 cells showed nucleosomal fragmentation, indicative of apoptosis. When assayed 2 days after adding bromocriptine, approximately 60% of GH3 and 58% of AtT-20 cells treated with bromocriptine displayed typical apoptotic morphology, including condensed chromatin and fragmented nuclei. There was a time dependent increase in the proportion of all tumour cells undergoing apoptosis. Decreased expression of bcl-2 and accumulation of wild-type p53 were associated with bromocriptine induced apoptosis in pituitary adenoma cells. DNA analysis confirmed the results obtained by the protein study. Different expression of p53 and bcl-2 genes is consistent with the expression of these gene products. These findings show that bromocriptine activated wild-type p53 and suppressed bcl-2 favouring occurrence of apoptosis in pituitary adenoma cells. Copyright 1999 Harcourt Publishers Ltd.
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PMID:Bromocriptine-induced apoptosis in pituitary adenoma cells: relationship to p53 and bcl-2 expression. 1084 57

The current model of human neoplasia invokes a number of potential genomic alterations that impact cellular phenotype and proliferative rates. In the majority of human tumor models, the transformation from normal cells to neoplastic lesion is a multistep process. This review offers a specific overview of the involvement of tumor suppressor genes (TSGs) in the pathogenesis of human pituitary adenomas. TSG genetic lesions, such as BRCA1 in breast cancer and p53 in Li-Fraumeni Syndrome, have been identified in both sporadic and heritable human endocrine tumors. Familial neoplastic syndromes like multiple endocrine neoplasia type 1 (MEN1) that include pituitary tumor formation as part of a broad clinical spectrum of disease represent a unique opportunity to investigate the general mechanisms of tumorigenesis, and well as genes responsible for sporadic endocrine tumors. Similarly, homologous recombination knockout mice with selectively ablated candidate TSGs have also shed light on the molecular mechanisms of pituitary cell proliferation and tumor suppression. However, despite insights into pituitary tumorigenesis generated by heritable neoplasia syndromes and mouse knockout of critical TSGs that display a pituitary tumor phenotype, the molecular pathogenesis of human pituitary adenomas remains largely an enigma. Thus, the role of TSGs, if any, in sporadic pituitary adenoma formation has yet to be determined, despite our greater understanding of the molecular mechanisms underlying pituitary cell function and phenotype.
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PMID:Tumor suppressor loss in pituitary tumors. 1141 76

Compatible with contemporary paradigms of the role of genetic aberrations in the progression of human tumors, the growth of pituitary tumors into a state of invasiveness appears to be due to genetic alterations. Amplification of H-ras and c-myc oncogenes and mutations of p53, nm23 and Rb genes have been identified disproportionately more in aggressive tumors and, in the case of Rb gene, in pituitary carcinomas, providing evidence that amplification of these oncogenes (H-ras and c-myc) and inactivation of tumor suppressor genes (p53, nm23 and Rb) seem to be at least one mechanism by which pituitary tumors progress. The current level of management of invasive pituitary adenomas should become more comprehensive as the advances in our understanding of genetic basis of pituitary adenoma invasiveness becomes translated into development of novel chemotherapy or gene transfer technique.
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PMID:Genetic basis of pituitary adenoma invasiveness: a review. 1151 49

Metastatic tumor to a pituitary adenoma has rarely been documented in the literature. We report a case of a 60-year-old man who presented with a history of progressive blurred vision and an incomplete homonymous hemianopsia. Magnetic resonance imaging showed a 5 cm heterogeneous mass which focally was contrast enhancing, involving the sella turcica and extending into the right cavernous sinus region. After worsening symptoms, repeat magnetic resonance imaging showed an increase in size of the lesion. Histologically, the mass consisted of a metastatic adenocarcinoma to a nonsecreting pituitary adenoma. The carcinoma stained focally positive with antibodies to carcinoembryonic antigen, cytokeratin 20, and p53 (60% of tumor cells), and did not stain with antibody to cytokeratin 7. The histologic appearance and immunohistochemical profile of the metastasis suggests a colorectal primary.
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PMID:Metastatic adenocarcinoma to a pituitary adenoma. 1174 74

To understand the relationship between pituitary adenoma and carcinoma, four adrenocorticotropic hormone-producing pituitary adenomas and corresponding metastatic carcinomas were studied. All were functional macroadenomas (three cases of Nelson syndrome and one of Cushing disease) that initially invaded the sella turcica and occurred in women ranging in age from 17 to 66 years (mean 45 years). Metastases (two craniospinal and two systemic) occurred after latency periods of 6 to 13 years. Histological specimens were immunostained for pituitary hormones, Ki-67 antigen (MIB-1), p53 and p27 proteins, D-type cyclins, and glucocorticoid receptor messenger (m)RNA. The DNA content of the specimens was assessed using Feulgen stain. Reactivities were quantified by digital image analysis. Primary/recurrent lesions and metastatic tumors differed according to their respective mean mitotic indices (1.2/10 hpf compared with 4.3/10 hpf), MIB-1 labeling (1.7% compared with 8%), p53 staining (37.3% compared with 49.9%), and p27 labeling (48% compared with 25%). Cyclin D, immunoreactivity provided no prognostically significant information. Glucocorticoid receptor mRNA was detected in all cases. Results of a ploidy analysis were variable and nonprognostic. In keeping with the 2000 World Health Organization classification of endocrine neoplasms, our findings support the concept that primary tumors that exhibit mitotic activity, an increased (> 3%) MIB-1 labeling index, and/or p53 immunoreactivity should be termed "atypical adenomas" to denote their aggressive potential and the possibility of future malignant transformation.
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PMID:Corticotroph carcinoma of the pituitary: a clinicopathological study. Report of four cases. 1183 11


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