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)

Thyroid malignancy has been induced by long-term endogenous thyrotropin (TSH) stimulation in experimental animals, leading to local and distant metastasis. It has been postulated that constant and prolonged endogenous TSH stimulation in dyshormonogenetic thyroid tissues could result in thyroid neoplasia. The possible role of growth factors and oncogenes in goitrogenesis and favoring neoplasia has also been mentioned. Overexpression of certain growth factors and/or their receptors, and of oncogenes implicated in growth promotion may play a significant role in the relatively frequent finding of thyroid malignancy in congenital goiters. In this study the expression of epidermal growth factor (EGF), epidermal growth factor receptor (EGF-R), transforming growth factor-beta (TGF-beta), c-myc, and p53 mRNAs was determined in 14 thyroid tissue samples: 6 from patients with thyroid peroxidase (TPO) gene mutations, 4 with thyroglobulin (Tg) gene defects and 4 normal thyroid tissues. EGF mRNA overexpression was seen in 7 of 10 dyshormonogenetic tissues (3.5 to 12.0 arbitrary optical densitometry units [AODU]) and considered significantly higher (p < 0.01) when compared to normal thyroid tissues (0.25 to 0.32 AODU). Moreover, overexpression of EGF-R mRNA was present in 6 of 10 dyshormonogenetic tissues (2.23 to 13.03 AODU) and considered significantly higher (p < 0.01) when compared to normal thyroid tissues (0.42 to 0.65 AODU). There was no difference in c-myc, p53, and TGF-beta mRNAs expression between dyshormonogenetic and normal tissues. The overexpression of EGF and EGF-R mRNAs found in dyshormonogenetic tissues may suggest that this growth factor may play a role in cellular proliferation and contribute to goiter formation.
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PMID:Overexpression of epidermal growth factor and epidermal growth factor-receptor mRNAs in dyshormonogenetic goiters. 1127 91

HER2 oncogene overexpression has been associated either with proliferation or differentiation and apoptosis. The role of p53 on these different chances was investigated. Wild type (wt) p53-IGROV1 cells showed growth inhibition and apoptosis after HER2 transfection, whereas no anti-proliferative effect was observed in its mutated p53 sub-line unless wt p53 was cotransfected with HER2. Stable HER2 transfectants derived from wt p53 line treated with heregulin-beta1 or epidermal growth factor showed a decrease in proliferation due to a G(2)/M cell cycle block despite normal mitogen-activated protein kinase activation. In these HER2 transfectants, c-Myc and p53 expression were increased, whereas MDM2 was dramatically down-modulated. By contrast, growth factors stimulation of HER2 transfectants with mutated-p53 induced progression through the cell cycle. Together, our data point to a regulatory role for p53 in HER2 signaling.
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PMID:Role of p53 in HER2-induced proliferation or apoptosis. 1127 58

Our previous studies have shown that overexpression of aromatase results in increased tissue estrogenic activity and induction of hyperplastic and dysplastic lesions in aromatase transgenic mammary glands. In this study, we have examined the effects of aromatase overexpression on biochemical changes in the aromatase transgenic mice. Our results show an increase in the expression of both estrogen and progesterone receptors, and their expression is maintained in the transgenic mammary tissue even without circulating ovarian estrogens. Our results also show an increase in the expression of several growth factors and cell cycle genes in the aromatase transgenic mammary glands, which is consistent with the observed increase in proliferating cell nuclear antigen levels and cellular proliferation. Interestingly, we have also observed a decrease in the expression of epidermal growth factor receptor and its ligands, epidermal growth factor and transforming growth factor alpha, as well as several tumor suppressor genes such as p53 and retinoblastoma. This study presents novel and interesting findings that are consistent with the current models of aromatase influence and the complex interactions of biochemical pathways leading to mammary tumorigenesis.
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PMID:Overexpression of aromatase leads to hyperplasia and changes in the expression of genes involved in apoptosis, cell cycle, growth, and tumor suppressor functions in the mammary glands of transgenic mice. 1128 Jul 46

We examined cell cycle-related effects of the phosphatase inhibitor okadaic acid (OA) in T51B rat liver epithelial cells under conditions chosen to mimic early stages of tumor promotion by this compound. Optimal transformation (colony formation in soft agar) was seen after prolonged culture of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-initiated T51B cells in 7 nM OA. Paradoxically, T51B cells treated with 2-10 nM OA showed decreased, rather than increased, proliferation in response to epidermal growth factor (EGF), as measured by [3H]thymidine incorporation. Complete inhibition was observed within 24 h at 10 nM OA. This response paralleled a loss of EGF-stimulated cdk2 kinase activity and an increase in association of the inhibitors p21 (cip-1) and p27 (kip-1) with cdk2. An increase in p53 phosphorylated on serine 15 accompanied the rise in p21 (cip-1). Both phosphorylation of the retinoblastoma protein and induction of cyclin A by EGF were blocked in cells treated with OA, but there was an increase in cyclin E. Resting cells treated with OA alone also showed elevated cyclin E levels, together with reduced levels of the E2F regulator pRb2/p130. Taken together, these observations indicate transforming levels of okadaic acid elicit a G(1)-trapping effect by facilitating cell cycle progression to the G(1)/S checkpoint, where cells are trapped by mechanisms that include p21 (cip-1)-mediated inhibition of cdk2. They support the premise that disruption of cellular processes regulating the transitions from G(0) to G(1) to S-phase is an important early step in tumor promotion by low levels of okadaic acid.
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PMID:Abbreviated cell cycle progression induced by the serine/threonine protein phosphatase inhibitor okadaic acid at concentrations that promote neoplastic transformation. 1147 Jul 44

BH3-only proteins function at a proximal point in a conserved cell death pathway by binding, through their BH3 domains, to other Bcl-2 family members and triggering mitochondrial events associated with apoptosis. Here, we describe a strongly pro-apoptotic BH3-only protein, designated Bbc3, whose expression increases in response to diverse apoptotic stimuli. bbc3 mRNA levels were induced by exposure to DNA-damaging agents and by wild-type p53, which mediates DNA damage-induced apoptosis. p53 transactivated bbc3 through consensus p53 binding sites within the bbc3 promoter region, indicating that bbc3 is a direct target of p53. Additionally, bbc3 mRNA was induced by p53-independent apoptotic stimuli, including dexamethasone treatment of thymocytes, and serum deprivation of tumor cells. Insulin-like growth factor-1 and epidermal growth factor, growth factors with broad anti-apoptotic activity, were each sufficient to suppress Bbc3 expression in serum-starved tumor cells. These results suggest that the transcriptional regulation of bbc3 contributes to the transduction of diverse cell death and survival signals.
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PMID:Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. 1157 83

Carcinogenesis involves a multistep process whereby a normal healthy cell undergoes both immortalization and oncogenesis to become fully transformed. Immortalization results from the subversion of critical cell cycle regulatory checkpoints, thereby allowing a cell to extend its finite life span and to maintain telomeric length. Oncogenesis is the manifestation of additional genetic events that are capable of conferring upon the cell an actual growth advantage. Such an advantage may relieve a cell of its normal requirements for a particular growth factor or may enhance the ability of a cell to proliferate outside of its normal microenvironment. To further investigate this multistep process, we developed an immortalized mammary epithelial cell line by overexpressing the catalytic subunit of telomerase (human telomerase reverse transcriptase) in primary human mammary epithelial cell lines. We present evidence that the overexpression of human telomerase reverse transcriptase was sufficient to extend the life span of the cells and allow for additional events that lead to immortalization. The result was the establishment of an IMEC line. Biochemical analysis of these cells indicates a basal epithelial phenotype with expression of high molecular weight cytokeratins. We show that continued growth of the IMECs is rigorously dependent upon both insulin and epidermal growth factor, and that the mitogenic effects of these factors on the IMECs are mediated in part by AKT. In addition, IMECs express the p53 family member DeltaN-p63-alpha, which is found in basal epithelial cells of many tissues and has been implicated as playing an essential role in normal epithelial development. Our studies suggest that the immortalization of basal epithelial cells of the mammary gland may be an early step in the initiation of a subset of breast cancers with a basal epithelial phenotype.
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PMID:Growth factor requirements and basal phenotype of an immortalized mammary epithelial cell line. 1178 64

We previously reported that the ErbB2 oncoprotein prolongs and amplifies growth factor signalling by impairing ligand-dependent downregulation of hetero-oligomerised epidermal growth factor receptors. Here we show that treatment of A431 cells with different epidermal growth factor receptor ligands can cause growth inhibition to an extent paralleling ErbB2 tyrosine phosphorylation. To determine whether such growth inhibition signifies an interaction between the cell cycle machinery and ErbB2-dependent alterations of cell signalling kinetics, we used MCF7 breast cancer cells (which express wild-type p53) to create transient and stable ErbB2 transfectants (MCF7-B2). Compared with parental cells, MCF7-B2 cells are characterised by upregulation of p53, p21(WAF) and Myc, downregulation of Bcl2, and apoptosis. In contrast, MCF7-B2 cells co-transfected with dominant negative p53 (MCF7-B2/Delta p53) exhibit reduced apoptosis and enhanced growth relative to both parental MCF7-B2 and control cells. These data imply that wild-type p53 limits survival of ErbB2-overexpressing breast cancer cells, and suggest that signals of varying length and/or intensity may evoke different cell outcomes depending upon the integrity of cell cycle control genes. We submit that acquisition of cell cycle control defects may play a permissive role in ErbB2 upregulation, and that the ErbB2 overexpression phenotype may in turn select for the survival of cells with p53 mutations or other tumour suppressor gene defects.
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PMID:Dominant negative knockout of p53 abolishes ErbB2-dependent apoptosis and permits growth acceleration in human breast cancer cells. 1195 57

Pancreatic cancer has a very poor prognosis and is a common cause of cancer death in the Western world. Certain genetic alterations may be important in the prognosis of pancreatic cancer. Activation mutations in the K- ras oncogene occur in around 90% of pancreatic cancers, and the overexpression of growth factors epidermal growth factor (EGF), transforming growth factor (TGF)alpha, TGFbetas 1-3, acidic fibroblast growth factor (aFGF), basic FGF (bFGF), and growth factor receptors c-erbB-2 and -3 and TGFRbetas 1-3 is common. High mutation levels of cell cycle control genes such as p53, p16, p21, SMAD4, and cyclin D1 are found, and there is abnormal expression of apoptotic genes, such as bcl-2, bcl-XL, and bax. The expression of several of these growth factors and their receptors has been found to be associated with poorly differentiated tumors of an advanced stage and decreased survival. However, the inactivation and loss of expression of p16, p53, and p21, and the expression of several apoptotic genes, such as bax and bcl-2, have not been found to be of any prognostic significance. The expression of wild type p53, however, may predict responsiveness to chemotherapy. TGFbeta1 expression has been shown to be associated with longer survival in patients with pancreatic cancer. Two studies (including our own) have found bcl-XL expression to be significantly associated with poor survival. These and newer molecular markers may prove to be important in the choice of future therapies for pancreatic cancer.
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PMID:Molecular prognostic markers in pancreatic cancer. 1202 93

The tumor suppressor gene, TP53, plays a major role in surveillance and repair of radiation-induced DNA damage. In multiple cell types, including mammary epithelial cells, abrogation of p53 (encoded by Trp53) function is associated with increased tumorigenesis. We examined gamma-irradiated BALB/c-Trp53(+/+) and -Trp53(-/-) female mice at five stages of post-natal mammary gland development to determine whether radiation-induced p53 activity is developmentally regulated. Our results show that p53-mediated responses are attenuated in glands from irradiated virgin and lactating mice, as measured by induction of p21/WAF1 (encoded by Cdkn1a) and apoptosis, while irradiated early- and mid-pregnancy glands exhibit robust p53 activity. There is a strong correlation between p53-mediated apoptosis and the degree of cellular proliferation, independent of the level of differentiation. In vivo, proliferation is intimately influenced by steroid hormones. To determine whether steroid hormones directly modulate p53 activity, whole organ cultures of mammary glands were induced to proliferate using estrogen plus progesterone or epidermal growth factor plus transforming growth factor-alpha and p53 responses to gamma-irradiation were measured. Regardless of mitogens used, proliferating mammary epithelial cells show comparable p53 responses to gamma-irradiation, including expression of nuclear p53 and p21/WAF1 and increased levels of apoptosis, compared to non-proliferating irradiated control cultures. Our study suggests that differences in radiation-induced p53 activity during post-natal mammary gland development are influenced by the proliferative state of the gland, and may be mediated indirectly by the mitogenic actions of steroid hormones in vivo.
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PMID:Epithelial cell cycling predicts p53 responsiveness to gamma-irradiation during post-natal mammary gland development. 1205 Jan 46

Pituitary carcinomas are only defined by their metastatic growth, which may be intracranial or systemic. To establish further morphological and immunohistochemical differences between pituitary carcinomas and adenomas, 19 ACTH-secreting adenomas (10 non invasive and 9 invasive) and 2 ACTH-secreting carcinomas with their metastases were studied for expression of the intermediate filaments keratin and vimentin and the tumor-associated antigens Ki67, proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF), cathepsin D, p53, and carcinoembryonic antigen (CEA). Immunohistochemistry was performed using avidin-biotin techniques on formalin-fixed, paraffin-embedded tissue. With the exception of one noninvasive pituitary adenoma, one carcinoma, and the metastases, all tumors contained keratin; none contained vimentin. All tumors stained negative for CEA and p53. Eleven (58.5%) adenomas and both pituitary carcinomas contained Ki67-positive nuclei; 14 (74%) adenomas and one carcinoma revealed PCNA. No correlation was found between the two markers. Seven (38%) adenomas showed a labeling index <1 % for cathepsin D, whereas none of the carcinomas or metastases did so. EGF was found in 7 (38%) adenomas and in both carcinomas. A tendency to a higher rate of EGF positivity in the invasive adenomas was observed. The metastases showed a higher labeling index, and far more intense staining results for Ki67, PCNA, and EGF than the primary tumor. The metastases also had a higher proliferation rate and growth factor content than the carcinoma itself.
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PMID:Proliferation Markers and EGF in ACTH-Secreting Adenomas and Carcinomas of the Pituitary. 1211 89


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