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

Kidney tubule cell line (TKC2) established from temperature-sensitive (ts) SV40 T-antigen gene transgenic mice exhibited cell death by apoptosis at nonpermissive temperature (39 degrees C). To learn how immortalization occurs, we generated T-antigen-independent immortalized cells (resistant clones) by culturing TKC2 cells at 39 degrees C. These independently isolated resistant clones exhibited ts properties in T-antigen and contained only wild-type p53. They grew similarly at 39 degrees and at 33 degrees C, but cell death was induced soon after they reached confluency at 39 degrees C. However, cell death was equally prevented by transfecting the bcl-2 gene. While TGF-beta showed no growth-suppressive effect in the sensitive and resistant clones at 33 degrees C, it induced significantly earlier cell death in the resistant clones at 39 degrees C. Thus, the resistant clones may be incompletely immortalized cell lines which induce cell death in response to the growth-suppressive effects of contact inhibition.
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PMID:Properties of incompletely immortalized cell lines generated from a line established from temperature-sensitive SV40 T-antigen gene transgenic mice. 764 84

The Hepatocyte growth factor is the most potent mitogen for hepatocytes in primary culture and is involved in liver regeneration. The expression of the gene appears to be tightly controlled by various humoral factors. To understand the molecular mechanism of the gene expression, we cloned and determined the nucleotide sequence of the 5'-flanking region of the gene. In this region, there are sequences homologous to responding elements of P53, Rb, IL-1, IL-6, glucocorticoids, TPA and TGF-beta. We also identified three major transcriptional initiation sites by primer extension analysis of this region. Functional analyses of this region by constructing CAT reporter plasmids indicate that the sequence functions in a tissue specific manner and there is a negative regulatory region which suppresses the gene expression in rat transformed kidney cells.
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PMID:Characterization of the 5'-flanking region of the hepatocyte growth factor gene. 768 37

A 24 hr TGF-beta 1 treatment (4 ng/ml) of SV40-transformed WI38 embryonic fibroblasts (VA13 cells) causes a moderate but reproducible inhibition of their serum-stimulated growth. By immunoprecipitation with the PAb122 antibody, we show that serum stimulation of previously serum-deprived cells causes a dephosphorylation of the wild type P53 protein, which is accentuated by the TGF-beta 1 treatment. The TGF-beta 1-enhanced dephosphorylation effect is also observed in two other cell lines growth-inhibited by TGF-beta 1, but which do not contain Large T (mink lung CCL64 and human KHOS cells). On the contrary, TGF-beta 1 treatment of the untransformed WI38 fibroblasts stimulates their growth, without affecting the phosphorylation of P53. Such treatment did not affect the expression of the corresponding mRNA nor the level of synthesis of the protein. The results suggest that the P53 protein could be a downstream target of TGF-beta 1 action on those cells growth-inhibited by the factor.
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PMID:Transforming growth factor-beta 1 enhances serum-induced dephosphorylation of the P53 protein in cell lines growth-inhibited by this factor. 773 45

Growth of thyroid cancer cells is stimulated by various growth factors via signal transduction pathways. TSH, EGF, IGF, and TGF-alpha stimulate and TGF-beta inhibits thyroid cell growth. TSH stimulates thyroid cells via both the adenylate cyclase-PKA and the PLC-PKC-Ca signal transduction pathways. TSH-r, ras, gsp, ret, trk, and myc are oncogenes that are activated in some thyroid neoplasms. P53 and RB are tumor suppressor genes that are inactivated in some thyroid cancers.
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PMID:Thyroid growth factors, signal transduction pathways, and oncogenes. 774 50

It has recently become clear that cyclin-dependent kinase (cdk) complex regulates the cell cycle by phosphorylating Rb protein, a tumor suppressor protein. It is likely that this complex is a target of various growth factors and anti-growth factors (UV, TGF-beta etc.) in keratinocyte (KC). It has also been suggested that abnormalities in the cell cycle regulating mechanism such as increased activity of cyclin-cdk due to mutation of p53, a tumor suppressor gene, and overexpression of cyclin D may be concerned with carcinogenesis of KC. Thus, recent studies indicate that the cyclin-cdk complex is a common target of proliferation and carcinogenesis in KC.
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PMID:Cell cycle regulators in the keratinocyte (cyclin-cdk). 775 27

The transforming growth factor beta s (TGF-beta s) are a group of multifunctional growth factors which inhibit cell cycle progression in many cell types. The TGF-beta-induced cell cycle arrest has been partially attributed to the regulatory effects of TGF-beta on both the levels and the activities of the G1 cyclins and their kinase partners. The activities of these kinases are negatively regulated by a number of small proteins, p21 (WAF1, Cip1), p27Kip1, p16, and p15INK4B, that physically associate with cyclins, cyclin-dependent kinases, or cyclin-Cdk complexes. p21 has been previously shown to be transcriptionally induced by DNA damage through p53 as a mediator. We demonstrate that TGF-beta also causes a rapid transcriptional induction of p21, suggesting that p21 can respond to both intracellular and extracellular signals for cell cycle arrest. In contrast to DNA damage, however, induction of p21 by TGF-beta is not dependent on wild-type p53. The cell line studied in these experiments, HaCaT, contains two mutant alleles of p53, which are unable to activate transcription from the p21 promoter when overexpressed. In addition, TGF-beta and p53 act through distinct elements in the p21 promoter. Taken together, these findings suggest that TGF-beta can induce p21 through a p53-independent pathway. Previous findings have implicated p27Kip1 and p15INK2B as effectors mediating the TGF-beta growth inhibitory effect. These results demonstrate that a single extracellular antiproliferative signal, TGF-beta, can act through multiple signaling pathways to elicit a growth arrest response.
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PMID:Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. 777 46

Transforming growth factor beta 1 (TGF-beta 1) can cause a cell-cycle arrest in G1. Inhibition of cyclin-dependent kinase 4 (cdk4) synthesis plays a significant role in the mechanism by which this cytokine causes G1 growth arrest. Deregulated expression of cdk4 confers resistance to TGF-beta 1. Here, we show that TGF-beta 1 down-regulates cdk4 expression by inhibiting its translation. Moreover, mutant p53 confers resistance to TGF-beta 1 by interfering with the down-regulation of cdk4 in response to the cytokine. In contrast, we demonstrate that wild-type p53 represses the translation of CDK4. Regulation of cdk4 synthesis by both p53 and TGF-beta 1 is mediated by the 5'-untranslated region of the CDK4 message. Thus, regulation of CDK4 translation may be involved in control of G1 progression by p53.
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PMID:p53-dependent repression of CDK4 translation in TGF-beta-induced G1 cell-cycle arrest. 785 94

To define the molecular changes occurring in endocrine tumours, we have analysed three human endocrine tumours established in our laboratory: BON, a functioning carcinoid tumour from the pancreas; SIM, a nonfunctioning carcinoid of the ileum; and STAN, a pheochromocytoma. A homozygous point mutation of the N-ras gene was identified at codon 61 in BON cells in conjunction with overexpression of N-ras mRNA and protein. BON cells also exhibited increased expression of c-myc and cdc2 kinase mRNA and protein; TGF-beta 1, p53 and retinoblastoma (RB) mRNA and protein levels were decreased. In addition, increased expression of the mdm2 oncogene and both the truncated and the wild-type RB protein were noted in BON. SIM cells exhibited moderately increased N-ras and c-myc mRNA levels along with decreased levels of RB mRNA and protein. Similar to BON and SIM, analysis of STAN showed increased N-ras and c-myc levels. Our data show multiple molecular changes in the three human endocrine tumours with the BON cell line exhibiting the most dramatic changes. Furthermore, our data suggest the existence of different molecular pathways in the pathogenesis of endocrine tumours. These cell lines will provide unique in vitro models to further analyse the significance of these molecular alterations.
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PMID:Analysis of multiple molecular changes in human endocrine tumours. 795 99

To study the contribution of autocrine and paracrine TGF-beta 1 to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-beta 1 gene were initiated in vitro with the v-rasHa oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v-rasHa-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well-differentiated papillomas. Malignant progression was not associated with mutations in the c-rasHa gene, alterations in p53 protein, or loss of responsiveness to TGF-beta 1. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling index in all tumors was reduced when TGF-beta 1 null fibroblasts formed the stroma. The null tumor cells could not accumulate TGF-beta 1 from the host, but grafts of uninitiated null keratinocytes, which formed a normal epidermis, became TGF-beta 1 positive even though they did not express TGF-beta 1 mRNA. These results demonstrate that autocrine TGF-beta 1 suppresses the frequency and rate of malignant progression, and that autocrine and paracrine TGF-beta 1 can have opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor cell progression appears to result from the inability of tumor cells to localize host-derived TGF-beta 1 by a mechanism that operates in normal cells.
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PMID:Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma. 795 7

The mechanism of growth inhibition by transforming growth factor (TGF)-beta 1 was investigated. We examined the growth inhibitory effects of TGF-beta 1 on human nasopharyngeal carcinoma (KB) cells which constitutively expressed p53. TGF-beta 1 suppressed the DNA synthesis of KB cells in a dose-dependent manner. It had minimal effect on adenovirus-2-transduced KB cells expressing either adenovirus early region 1B (E1B) or 1A (E1A) product, which respectively binds to p53 or Rb product and inhibits its function, and no growth inhibition at all was observed with KB cells expressing both E1B and E1A products. Dephosphorylation of the p53 was promoted by TGF-beta 1 stimulation in KB cells, but not in E1B-producing KB cells, which sequestrate the function of p53. The growth inhibition of KB cells by TGF-beta 1 was significantly reduced by treatment with okadaic acid. These results suggest that p53 transduces the antiproliferative signal of TGF-beta 1 possibly through its dephosphorylation.
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PMID:Close correlation between the dephosphorylation of p53 and growth suppression by transforming growth factor-beta 1 in nasopharyngeal carcinoma cells transduced with adenovirus early region genes. 801 2


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