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)

Mouse mammary epithelial cells (MMEC) isolated from normal virgin BALB/c female mice and grown in cell culture for various lengths of time were injected into the mammary fat pads of syngenic mice. Of the ductal outgrowths which resulted from the injected MMEC, four gave rise to outgrowths that were serially transplanted beyond the lifetime of normal ductal outgrowths. The lifetime of normal ducts is five or six transplant generations. The four ductal outgrowth lines, termed EL for 'extended life', have been serially transplanted for 7, 9, 13 and 14 transplant generations. The outgrowths are predominantly ductal in morphology, do not exhibit intraductal epitheliosis characteristic of ductal hyperplasias, are ovarian dependent for growth and are responsive to prolactin-mediated alveolar differentiation. Three of the EL lines, EL5, 7 and 11 have not produced any tumors spontaneously (0/64) and only one tumor after dimethylbenz[a]anthracene (DMBA) treatment (1/30). The fourth line, EL12, differs from the other three in the presence of a limited degree of alveolar differentiation. The EL12 line has not produced any spontaneous tumors (0/23) but is somewhat more responsive to DMBA (3/10). We interpret the EL lines (at least EL11 and EL12) to represent cell populations where the immortalized phenotype is dissociated from the hyperplastic phenotype which is characteristic of mouse mammary preneoplastic populations. The tumor suppressor gene, p53, is not overexpressed in the EL ductal outgrowths. To our knowledge, this is the first example of cell populations in vivo that are immortalized but otherwise normal. As such, they may represent the earliest stage observable in the genesis of mouse mammary tumors and provide unique cell populations to examine molecular alterations associated with the property of immortality.
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PMID:Immortalization phenotype dissociated from the preneoplastic phenotype in mouse mammary epithelial outgrowths in vivo. 842 68

The purpose of this study was to investigate a prognostic indicator that can differentiate node negative breast cancer patients (N = 39, T2N0M0) with high risk and low risk for the development of recurrence or metastases. Preoperative plasma prolactin (PRL) was estimated by radioimmunoassay. The expression of PRL, p53, nm23, and c-erbB2 was investigated by immunohistochemical (IHC) localization; cathepsin D (CD, Enzyme Linked Sorbant Assay) and estrogen- and progesterone-receptors (ER and PR, Dextran coated charcoal method) were estimated in the tumor cytosols. The follow-up period was 2-6 years. Statistical comparisons were made between each marker for relapse-free survival (RFS) and overall survival (OS). Of the 39 patients, 18 had hyperprolactinemia (PRL > 20.0 ng/ml plasma), whereas overexpression of p53 was observed in 55% (17/31) tumors. These were independently and in combination associated with a reduced RFS and OS. The rest of the investigated markers did not show promising results. Hyperprolactinemia and/or overexpression of p53 were associated with aggressiveness of the tumor, early disease relapse or metastases, and poor OS in patients with node negative breast cancer. These two markers may enhance our ability to identify node negative breast cancer patients with aggressive tumors, for whom the use of adjuvant chemo and/or endocrine therapy is unequivocally justified.
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PMID:Node negative breast carcinoma: hyperprolactinemia and/or overexpression of p53 as an independent predictor of poor prognosis compared to newer and established prognosticators. 864 46

The term "nonfunctioning" pituitary adenomas (NFPA) implies heterogeneity, since it relies on a clinical definition that is mainly related to tumor mass. The first complaint is often of impaired visual function, and despite the secretion of gonadotropins, hypogonadism is frequent. NFPA must be differentiated from prolactinomas, because of the therapeutic implications, but although prolactin (PRL) levels greater than 200 ng/mL indicate prolactinoma, PRL levels of 100 to 150 ng/mL are equivocal. An assessment of gonadotropin response to gonadotropin-releasing hormone (GnRH) is of no use, but the thyrotropin-releasing hormone (TRH) test is invaluable. NFPA are monoclonal in origin, but genetic mutations data have not clarified their etiology, which remains largely unknown. Proliferating cell nuclear antigen expression is increased in recurrent adenomas, as is abnormality and overexpression of the protein kinase C family in aggressive tumors. Mutations of tumor-suppressor genes, such as the p53 and Rb genes, and of the metastasizing suppressor gene nm23, have been found in invasive tumors. Immunohistochemistry data confirm that most NFPA originate from gonadotroph cells; many NFPA are negative for all anterior pituitary hormones tested, although isolated or clustered cells are often positive for glycoprotein hormones or their subunits. Silent gonadotroph and also silent growth hormone (GH) or corticotroph tumors can constitute the anatomical basis for clinical NFPA. The heterogeneity of the immunohistochemistry data is reflected in the receptor complex of these tumors. Dopaminergic receptors have recently been visualized in vivo and there are also receptors for TRH or GnRH, since levels of alpha or beta subunits and intact gonadotropins increase after TRH or GnRH stimulation. As a result, three second-line pharmacological approaches have been tried: dopamine agonists, octreotide, and GnRH superagonists or antagonists, with tumor shrinkage of up to 11% to 20%. However, surgery should be tried first.
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PMID:Nonfunctioning adenomas of the pituitary. 876 90

The induction of the transcription factor Sp1 by prolactin (PRL) and interleukin-2 (IL-2) was investigated in the PRL- and IL-2 responsive rat Nb2 T-cell line. Western analysis showed a rapid increase in Sp1 synthesis in Nb2 cells in response to PRL or IL-2. Elevation of Sp1 protein levels occurred within 15 min following PRL or IL-2 stimulation, reached a maximum by 1 h and was inhibited by cycloheximide, indicating de novo protein synthesis. Interestingly, dilution of confluent, growth-arrested Nb2 cells to low density also caused a rapid elevation in Sp1 suggesting that growth arrest may down-regulate Sp1 synthesis. Electrophoretic mobility shift assays using an Sp1 consensus oligonucleotide as probe showed a rapid but transient formation of a single PRL-inducible complex at 30 min. In contrast, three IL-2-inducible complexes were formed at 30 min and persisted to at least 60 min. Mobility shift interference assays using specific Stat antibodies failed to detect Stat1alpha, Stat3 or Stat5 in the 30 min PRL-inducible complex. In contrast, the IL-2 induced complexes contained Stat3 alone at 30 min and both Stat3 and Stat5 at 60 min. The PRL- and IL-2-inducible complexes did not contain the tumor suppressor protein, p53. The time dependent association of the Stat proteins with the IL-2-inducible complexes, but not with the PRL-inducible complex, suggests that the two mitogens may selectively utilize specific promoter elements for transcriptional activation of PRL- and IL-2-responsive genes. Alternatively, the two mitogens may be activating different genes with Sp1-binding promoter elements for their mitogenic action in Nb2 cells.
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PMID:Induction of Sp1 activity by prolactin and interleukin-2 in Nb2 T-cells: differential association of Sp1-DNA complexes with Stats. 917 24

A 49-yr-old woman presented with an extensive prolactinoma (serum PRL > 10,000 mU/L, normal range < 450 mU/L). Over a 5-yr period following transsphenoidal surgery and pituitary irradiation, she became increasingly resistant to high doses of bromocriptine and underwent transfrontal surgery followed by stereotactic radiotherapy. In spite of these treatments, serum prolactin estimations rose progressively to > 100,000 mU/L. Magnetic resonance imaging scanning demonstrated a massive cystic tumor invading the temporal lobes, extending into the cervical and thoracic spine, with metastases to cervical lymph nodes. High-dose cabergoline administration resulted in a 30% decrease in serum PRL. Octreotide was administered as a continuous sc infusion with a profound analgesic effect on facial pain but with no effect on tumor progression. She was treated with a course of chemotherapy consisting of carboplatin and etoposide without any noticeable effect. The patient died 6 months following chemotherapy. Immunocytochemical analysis demonstrated positive nuclear staining for WAF-1, Rb protein, c-myc, and p53 both in the original and metastatic tumors. The metastases but not the primary tumor stained for c-jun. Metastatic prolactinoma remains a therapeutic challenge. It is associated with a variable proto-oncogene expression, which may be coincidental or causal. Cabergoline had no advantage over bromocriptine. Octreotide relieved facial pain but did not alter tumor progression. An effective therapy for metastatic prolactinoma remains to be identified.
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PMID:Metastatic prolactinoma: effect of octreotide, cabergoline, carboplatin and etoposide; immunocytochemical analysis of proto-oncogene expression. 928 27

Trophoblast giant cell differentiation is characterized by endoreduplication and expression of members of the prolactin (PRL) gene family and can be simulated in vitro via manipulations of the Rcho-1 trophoblast cell line. The regulation of trophoblast cell proliferation and differentiation involves tyrosine protein kinase signaling pathways. Treatment of Rcho-1 trophoblast cells with tyrosine kinase inhibitors disrupted differentiation-dependent expression of members of the PRL gene family and cytoskeletal organization. Activated p60c-src, p62c-yes, and p53/56lyn were present in the Rcho-1 rat trophoblast cell line and in differentiated trophoblast cells isolated from the developing rat placenta. p60c-src and p62c-yes were active in proliferating and differentiating trophoblast cells. During proliferation, p62c-yes exhibited distinct associations with other phosphoproteins (34, 66, 76, and 150 kDa). p53/56lyn was activated only in differentiating trophoblast cells. p53/56lyn showed a differentiation-dependent accumulation in cytoskeletal and membrane fractions, whereas p60c-src levels were virtually invariant in both fractions. Expression patterns of csk, a negative regulator of Src family kinase activities, were not consistent with its involvement in the differentiation-dependent activation of p53/56lyn; however, there was some indication of the participation of a tyrosine phosphatase in the regulation of p53/56lyn. In conclusion, p60c-src, p62c-yes, and p53/56lyn patterns of activation in trophoblast cells are consistent with their involvement in the control of trophoblast cell proliferation and differentiation.
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PMID:Signaling pathways controlling trophoblast cell differentiation: Src family protein tyrosine kinases in the rat. 940 34

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

p53 is a tumor suppressor which exerts its function through the regulation of genes mediating cell cycle arrest and the induction of apoptosis. Cellular survival and proliferation can be positively regulated through the action of cytokines. These signals act through the activation of cell surface receptors, and the phosphorylation of intracellular signaling components, e.g. members of the Stat family (signal transducers and activators of transcription). The signaling effects of p53 and the cytokine receptors on the cellular phenotype are counteracting. We investigated the influence of p53 on the transactivation potential of Stat5. p53 repressed the prolactin induction of the Stat5 mediated transcription of the beta-casein promoter-luciferase reporter gene, but did not affect IFN-gamma induced, Stat1 dependent transcription of the IRF-1 promoter. The inhibition was not due to a decrease in the cellular concentration of Stat5 or to interference with its specific DNA binding activity. No repression of the basal transcriptional activity of the beta-casein promoter was observed. p53 mutants defective in their DNA binding or oligomerization functions had only weak inhibitory effects, but a mutant of p53 in the transactivation domain, efficiently repressed Stat5 dependent induction. The repressive function of p53 on Stat5 activity is independent of the amino-terminal transactivation domain, but requires a functional DNA binding domain and the carboxyl-terminal domain. Our experiments show that p53 counteracts Stat5 mediated cytokine induction of gene transcription. The effect is specific for Stat5 and independent of p53 induced apoptosis.
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PMID:p53 suppresses cytokine induced, Stat5 mediated activation of transcription. 980 59

Multiple endocrine neoplasia type 1 (MENI) is a promising model to understand endocrine and other tumors. Its most common endocrine expressions are tumors of parathyroids, entero-pancreatic neuro-endocrine tissue, and anterior pituitary. Recently, collagenomas and multiple angiofibromas of the dermis also have been recognized as very common. MEN1 can be characterized from different perspectives: (a) as a hormone (parathyroid hormone, gastrin, prolactin, etc.) excess syndrome with excellent therapeutic options; (b) as a syndrome with sometimes lethal outcomes from malignancy of entero-pancreatic neuro-endocrine or foregut carcinoid tissues; or (c) as a disorder than can give insight about cell regulation in the endocrine, the dermal, and perhaps other tissue systems. The MEN1 gene was identified recently by positional cloning, a comprehensive strategy of narrowing the candidate interval and evaluating all or most genes in that interval. This discovery has opened new approaches to basic and clinical issues. Germline MEN1 mutations have been identified in most MEN1 families. Germline MENI mutations were generally not found in families with isolated hyperparathyroidism or with isolated pituitary tumor. Thus, studies with the MENI gene helped establish that mutation of other gene(s) is likely causative of these two MEN1 phenocopies. MEN1 proved to be the gene most frequent L4 mutated in common-variety, nonhereditary parathyroid tumor, gastrinoma, insulinoma, or bronchial carcinoid. For example, in common-variety parathyroid tumors, mutation of several other genes (such as cyclin D1 and P53) has been found, but much less frequently than MEN1 mutation. The majority of germline and somatic MEN1 mutations predicted truncation of the encoded protein (menin). Such inactivating mutations strongly supported prior predictions that MEN1 is a tumor suppressor gene insofar as stepwise mutational inactivation of both copies can release a cell from normal growth suppression. Menin is principally a nuclear protein; menin interacts with junD. Future studies, such as discovery of menin's metabolic pathway, could lead to new opportunities in cell biology and in tumor therapy.
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PMID:The gene for multiple endocrine neoplasia type 1: recent findings. 1042 35

Twenty-seven plurihormonal and 21 growth hormone- prolactin- (GH- PRL-) mixed cell adenomas obtained from patients with acromegaly undergoing transnasal-transsphenoidal surgery were investigated immunohistochemically for expression of Epidermal Growth Factor (EGF), Transforming Growth Factor alpha (TGF alpha), Insulin-like Growth Factor-1 (IGF-1), Estrogen Receptor-Related Protein (ERRP), Multidrug Resistance Marker (MDRM), Protein Kinase C (PKC), Gs alpha,. Cathepsin D and p53. Five plurihormonal adenomas grew invasively. The panel of markers used in this study represents a selection of functional and proliferative markers thought to be associated with the function and development of pituitary adenomas. Our results imply that the growth factors (EGF, TGF alpha, IGF-1), the cell signalling protein Gs alpha and the MDRM are expressed by both types of pituitary adenomas in a similar pattern. Non-invasive GH-PRL-mixed cell adenomas showed an increased expression of IGF-1, TGF alpha and MDRM compared to non-invasive plurihormonal adenomas. No factor was found which would reliably distinguish between invasive and non-invasive adenomas. We failed to confirm the findings of others that p53 and cathepsin D might be indicators of tumor aggressiveness. A participation of ERRP and PKC in the development of bi- and plurihormonal adenomas with acromegaly appears unlikely, as the immunostains were all negative.
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PMID:Markers of function and proliferation in non-invasive and invasive bi- and plurihormonal adenomas of patients with acromegaly: an immunohistochemical study. 1050 79


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