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

Infection of quiescent cells with the DNA tumor virus simian virus 40 induces expression of the cellular thymidine kinase (TK) gene a minimum of 10- to 20-fold, and this induction depends upon the viral protein large T antigen (T-Ag). To define both human TK promoter elements and T-Ag functional domains required for transcriptional induction, we have established a system in which stable Rat-1 transfectants harboring TK promoter-luciferase hybrid genes are infected with recombinant adenoviruses expressing either wild-type or mutant forms of T-Ag and luciferase expression is measured as an indicator of promoter activity. The results show that (i) a 135-bp TK promoter fragment is activated 10- to 15-fold by viral infection; (ii) this activation is the result of both T-Ag-dependent and -independent mechanisms; (iii) the T-Ag pRb family-binding domain, but not the p53-binding, helicase, or ATPase domain, is required for activation; and (iv) activation is severely diminished with a TK promoter fragment in which E2F-like-binding sites have been removed. These data demonstrate a requirement for both an E2F-related factor and a pRb family member in activation of the TK promoter by T-Ag. This contrasts with the promiscuous activation of many cellular and viral genes by T-Ag, which is independent of its ability to bind pRb.
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PMID:Activation of the human thymidine kinase (TK) promoter by simian virus 40 large T antigen requires both the T antigen pRb family-binding domain and TK promoter sequences resembling E2F-binding sites. 870 58

Functional differentiation of mammary tissue progresses in distinct phases spanning puberty and pregnancy. Here we have analyzed and compared the effects of transforming growth factor beta 1 (TGF beta 1), TGF alpha, and whey acidic protein (WAP), the Notch-related cell fate protein Int3, and p53 and pRb on mammary development. We chose transgene expression from the WAP gene promoter which is only active in mammary alveolar cells. The imbalanced expression of these molecules specifically altered development and differentiation of the gland. While TGF alpha did not disturb alveolar outgrowth, little or no alveolar structures developed in the presence of Int3. TGF beta 1, WAP, and the expression of SV40 T-antigen-which inactivates p53 and PRb-reduced overall alveolar development. The expression of individual milk protein genes was affected differentially by the transgenes. A WAP-lacZ transgene served as an additional indicator of terminal differentiation of alveolar cells, Homogeneous expression of lacZ was seen in mice transgenic for lacZ, or for TGF alpha and lacZ. In contrast, only a few differentiated cells were observed in the presence of TGF beta 1 and Tag. Thus, the expression of growth regulators in the same defined subset of mammary cells results in distinct developmental changes and a specific pattern of alveolar differentiation.
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PMID:Understanding mammary gland development through the imbalanced expression of growth regulators. 872 83

The retinoblastoma gene (Rb) was the first tumor suppressor gene to be cloned [Dryja et al., 1986; Friend et al., 1986; Lee et al., 1987], and, as a consequence, has been studied intensively within the context of cell cycle regulation and oncogenesis. However, a number of recent findings indicate that the retinoblastoma gene product (pRb) likely plays an essential role not only in controlling entry into the cell cycle, but also in the terminal differentiation of a number of different cell types [Lee et al., 1994; Gu et al., 1993]. In particular, the phenotype of the Rb nullizygous mice, created by a number of groups using homologous recombination [Jacks et al., 1992: Clarke et al., 1992; Lee et al., 1992], indicates that pRb is essential for normal development of the nervous and hematopoietic systems and may even function to regulate apoptosis [Haas-Kogan et al., 1995]. Although this paper briefly reviews the traditional role of pRB in regulation of cellular proliferation, we focus on the role of pRB in neuronal development and apoptosis. Recent reviews have been published on the role of pRb in cell cycle and transcriptional regulation [Hamel et al., 1992; Cobrinik et al., 1992; Kouzarides, 1993; Hollingsworth et al., 1993; Helin and Harlow, 1993; Sherr, 1994], as well as the relationship between pRb and p53 [Picksley and Lane, 1994; White, 1994].
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PMID:Retinoblastoma gene in mouse neural development. 874 37

Rat fibroblasts transformed by a temperature-sensitive mutant of murine p53 undergo a reversible growth arrest in G1 at 32.5 degrees C, the temperature at which p53 adopts a wild-type conformation. The arrested cells contain inactive cyclin-dependent kinase 2 (cdk2) despite the presence of high levels of cyclin E and cdk-activating kinase activity. This is due in part to p53-dependent expression of the p2l cdk inhibitor. Upon shift to 39 degrees C, wild-type p53 is lost and cdk2 activation and pRb phosphorylation occur concomitantly with loss of p2l. This p53-mediated growth arrest can be abrogated by overexpression of cdk4 and cdk6 but not cdk2 or cyclins, leading to continuous proliferation of transfected cells in the presence of wild-type p53 and p2l. Kinase-inactive counterparts of cdk4 and cdk6 also rescue these cells from growth arrest, implicating a noncatalytic role for cdk4 and cdk6 in this resistance to p53-mediated growth arrest. Aberrant expression of these cell cycle kinases may thus result in an oncogenic interference with inhibitors of cell cycle progression.
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PMID:Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases. 875 45

Many human tumours are hyperdiploid, particularly in advanced stages of growth. The purpose of the present work was to investigate whether exposure to hypoxia followed by reoxygenation might induce hyperploidisation of diploid human tumour cells in vitro. The investigation was performed by using the diploid melanoma cell line BEX-c (median chromosome number, 46; DNA index, 1.10 +/- 0.04) as test line and the hyperdiploid melanoma cell line SAX-c (median chromosome number, 61; DNA index, 1.42 +/- 0.03) as control line. Cell cultures kept in glass dishes in air-tight steel chambers were exposed to hypoxia (O2 concentrations < 10 p.p.m. or < 100 p.p.m.) at 37 degrees C for 24 h. DNA content was measured by flow cytometry. Metaphase spreads banded with trypsin-Versene-Giemsa were examined to determine the number of chromosomes per cell. An electronic particle counter was used to measure cell volume. The expression of p53 and pRb was studied by Western blot analysis. Transient exposure to hypoxia was found to induce a doubling of the number of chromosomes in BEX-c but not in SAX-c. The fraction of the BEX-c metaphase spreads with 92 chromosomes was approximately 10% at 18 h after reoxygenation, decreased to approximately 2% at 7 days after reoxygenation and then increased gradually with time. The whole cell population became tetraploid within 25 weeks. BEX-c and SAX-c behaved differently during the 24 h hypoxia exposure. Cell volume and fraction of cells in G2 + M increased with time in BEX-c but remained essentially unchanged in SAX-c. On the other hand, the expression of p53 and pRb was similar for the two lines; hypoxia induced increased expression of p53 and hypophosphorylation of pRb.
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PMID:Hypoxia-induced tetraploidisation of a diploid human melanoma cell line in vitro. 876 66

The disruption of cell cycle regulation is associated with developmental abnormalities and tumorigenesis. The SV40 large T antigen (Tag) interferes with cell cycle control by interacting with the pRb family and p53. Mice carrying a transgene composed of the whey acidic protein (WAP) gene promoter and the Tag coding sequence express Tag during pregnancy and are unable to nurse their young. Tag expression induced apoptosis in mammary epithelial cells during late pregnancy. At least 5% of mammary epithelial cells were undergoing apoptosis at any one time. In contrast, less than 0.2% of mammary epithelial cells in nontransgenic littermates was undergoing apoptosis. Apoptosis in Tag mice was associated with increased steady-state RNA levels of bax and bcl-xL + S, with a relative increase in bcl-xs expression. Since p53 was sequestered by Tag, it is likely that p53-independent mechanisms precipitated apoptosis. The Tag-expressing mammary alveolar cells that did not undergo apoptosis continued to differentiate through late pregnancy, as measured by the sequential activation of milk protein gene expression. However, milk protein production, processing, and secretion was impaired, resulting in lactation failure.
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PMID:Expression of a viral oncoprotein during mammary gland development alters cell fate and function: induction of p53-independent apoptosis is followed by impaired milk protein production in surviving cells. 878 28

Previous studies have shown that simian virus 40 large T antigen transforms cells by binding and inactivating suppressors of cell cycle progression and tumor formation. Here, we characterize the interactions of five temperature-sensitive T antigens with the tumor suppressor proteins pRb and p53. All five mutant T antigens bind pRb at the nonpermissive temperature with efficiencies similar to that of wild-type T antigen. A single transformation-competent mutant, with a substitution of amino acid 186, binds p53 at the nonpermissive temperature. Four transformation-defective mutants, with a substitution at T antigen position 357, 422, 427, or 438, are temperature sensitive for the binding and inactivation of p53. Our findings provide a basis for understanding the behavior of cells transformed by temperature-sensitive T antigens.
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PMID:Differential interaction of temperature-sensitive simian virus 40 T antigens with tumor suppressors pRb and p53. 879 71

Deregulation of cyclin, cyclin-dependent kinases (CDKs) and their inhibitors could have a pivotal role in the development of diverse human cancers. We examined the genetic status and the expression of CDK inhibitors (p21, p27, p16 and p15), CDK2 and cyclins (A, D1 and E) in eight gastric carcinoma cell lines, in comparison with the status of p53 gene alterations. All the cell lines (except MKN-28) that contained a p53 gene abnormality expressed very low or undetectable levels of p21 mRNA, while the cell lines (MKN-45 and -74) with wild-type p53 gene expressed high levels of p21 mRNA. An inverse correlation was found between the level of p21 mRNA and the expression of mRNAs for CDK2 and G1 cyclins. MKN-28 was an exception; it contained mutated p53, and expressed mRNAs for p21, CDK2 and G1 cyclins at high levels. Only MKN-45 and -74, with wild-type p53, expressed considerable levels of p21 protein. Homozygous deletion of the p16 and p15 genes was detected in two (MKN-45 and HSC-39) of the eight gastric carcinoma cell lines, p16 protein was not expressed in three cell lines (MKN-28, MKN-74 and KATO-III), as well as MKN-45 and HSC-39. Rearrangement of the p15 gene was found in TMK-1. Rearrangement of the p27 gene was detected in MKN-45, although the expression of p27 protein was well preserved in all the gastric carcinoma cell lines. The expression of pRb was also preserved in all the cell lines except KATO-III. No obvious correlation was observed between the p53 gene status and the expression of p27 and p16. These findings suggest that abnormal regulation of CDK2/cyclins and CDK inhibitors might be involved in deregulated growth of gastric carcinomas.
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PMID:Genetic status and expression of the cyclin-dependent kinase inhibitors in human gastric carcinoma cell lines. 879 88

Alterations in the p53 tumor suppressor gene have been implicated in the genesis and/or progression of the majority of human cancers, including osteosarcoma. Stabilization of the protein by mutation or interaction with other proteins prolongs its half-life, rendering it detectable by immunohistochemistry. Osteosarcoma is the most common primary canine bone tumor and is characterized by frequent early metastases. Multilobular tumors of bone involve primarily flat bones of the head and are low-grade malignancies with lower metastatic potential. The objectives of this study were to determine the prevalence of p53 protein overexpression in 106 osteogenic tumors of dogs using an indirect immunohistochemical method and to compare p53 overexpression between tumors with different clinical behavior. A polyclonal p53 antibody (CM-1) served as the primary antibody. Tumors were scored based upon an estimate of the percentage of tumor cells stained. Significant differences in the prevalence of overexpression were observed between osteosarcomas (72%) and multilobular tumors of bone (20%, P = 0.0020). Osteosarcomas of the appendicular skeleton had a significantly higher prevalence of p53 overexpression (84%) than did osteosarcomas of the axial skeleton (56%, P = 0.0060). Our results show that p53 tumor suppressor protein is overexpressed in the majority of canine osteosarcomas. The higher prevalence of overexpression in osteosarcomas versus multilobular tumors of bone and in osteosarcomas of the appendicular skeleton versus those of the axial skeleton suggests that alterations in p53 expression correlate with highly aggressive tumor behavior.
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PMID:p53 tumor suppressor protein overexpression in osteogenic tumors of dogs. 880 15

The cellular transcription factor DRTF1/E2F and the tumor suppressor protein p53 play important roles in controlling early cell cycle events. DRTF1/E2F is believed to coordinate and integrate the transcription of cell cycle-regulating genes, for example, those involved in DNA synthesis, with the activity of regulatory proteins, such as the retinoblastoma tumor suppressor gene product (pRb), which modulate its transcriptional activity. In contrast, p53 is thought to monitor the integrity of chromosomal DNA and when appropriate interfere with cell cycle progression, for example, in response to DNA damage. Generic DRTF1/E2F DNA binding activity and transcriptional activation arise when members of two distinct families of proteins, such as DP-1 and E2F-1, interact as DP/E2F heterodimers. In many cell types, DP-1 is a widespread component of DRTF1/E2F DNA binding activity which when expressed at high levels oncogenically transforms embryonic fibroblasts. Here, we document an association between DP-1 and p53 and demonstrate its presence in mammalian cell extracts. In vitro p53 interacts with an immunochemically distinct form of DP-1 and in vivo can regulate transcription driven by the DP-1/E2F-1 heterodimer. At the biochemical level, p53 competes with E2F-1 for DP-1, with a consequent reduction in DNA binding activity. Mutational analysis defines within DP-1 a C-terminal region required for the interaction with p53 and within p53 an N-terminal region distinct from that required to bind to MDM2. Our results establish DRTF1/E2F as a common cellular target in growth control mediated through the activities of pRb and p53 and suggest an alternative mechanism through which p53 may regulate cellular proliferation.
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PMID:Functional interaction between DP-1 and p53. 881 2


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