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

Simian virus 40 (SV40) can promote cell transformation and suppress differentiation. It does this partly by targeting tumor suppressors such as p53 and members of the retinoblastoma susceptibility protein (Rb) family. This work concentrates on mechanisms by which SV40 large tumor antigen (SVLT) suppresses adipocyte differentiation. We created cell lines derived from murine 3T3-L1 preadipocytes expressing different versions of SV40 early-region sequences. SVLT-expressing cells failed to exhibit adipocyte morphology, to induce glycerophosphate dehydrogenase activity, and to induce differentiation-dependent mRNA for adipocyte P2. SVLT alone was sufficient, in the absence of SV40 small tumor antigen, to inhibit differentiation. A truncated SVLT containing only the N-terminal 121 amino acids (SVLT1-121) blocked differentiation, thus mapping at least one differentiation blocking function to the N-terminal region. K1 (Glu-107-->Lys) point mutants of SVLT, which are unable to bind to the Rb protein family or induce neoplastic transformation, are defective for blocking differentiation in the case of SVLT1-121 but retain the ability to block differentiation in the case of full-length SVLT. This finding demonstrates that Rb family proteins are important in regulating adipocyte differentiation but that other functions of full-length SVLT can block adipocyte differentiation independently of RB family binding and transformation.
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PMID:The block of adipocyte differentiation by a C-terminally truncated, but not by full-length, simian virus 40 large tumor antigen is dependent on an intact retinoblastoma susceptibility protein family binding domain. 855 11

The activity of the p53 tumor suppressor protein is regulated, at least in part, through the stability of the protein. p53 degradation in normal cells is controlled by ubiquitin-dependent proteolysis, and activation of p53 following DNA damage is associated with an increase in the stability of the protein. The human papillomavirus-encoded E6 protein abrogates p53 function by targeting it for rapid degradation, also through the ubiquitin pathway. Although the p53 protein is ubiquitinated following interaction with E6, we show here that none of the lysine residues within p53 are specifically required for E6-targeted degradation. Mutation of lysine residues within the C-terminus of p53 resulted in resistance to E6-mediated degradation in vitro, although the ability of the two proteins to form a complex was not affected. The same mutant was efficiently targeted for degradation in cells, however, illustrating a lack of correlation between the in vitro and the in vivo assays.
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PMID:Sensitivity of p53 lysine mutants to ubiquitin-directed degradation targeted by human papillomavirus E6. 859 13

Exons 5-7 of the tumour suppressor gene p53 were investigated in genomic DNA of tumours of domestic cats. In one fibrosarcoma investigated we observed a mutation GAG-->AAG (glutamic acid-->lysine) in codon 180; in another there was a mutation CGG-->TGG (arginine-->tryptophane) in codon 248.
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PMID:Mutations in tumour suppressor gene p53 in two feline fibrosarcomas. 860 83

Cancer-related mutations of the p53 tumor suppressor gene are clustered in the four so-called 'hot spots', codons 175, 248, 273 and 281/282. By using recombination PCR in vitro mutagenesis, we introduced point mutations into the codon 273 of wild-type (wt) p53 (pC53-SN3) from Arg to His (pC53-273H [273H]), Asp (273D), Pro (273P), Lys (273K), Leu (273L) or Thr (273T), and compared their biological and biochemical activities with wt p53 and cancer-derived 175H, 248W and 273H/309S. Among them, 273H/309S, 273H and 273D as well as wt p53 transactivated the chloramphenicol acetyltransferase (CAT) gene placed downstream of the p53 binding consensus, while none of the other mutants including 273L did. Transcriptions from human c-fos and rat PCNA promoters were suppressed by wt p53 and 273D, while they were enhanced variously by all other mutants in Saos-2 and/or NIH3T3 cells. On the other hand, growth of human squamous carcinoma cell lines measured by the plating efficiency of G418-resistant colonies was enhanced by transfection of 175H, 248W, 273H/309S and 273P, while suppressed by not only wt p53, 273D and 273H but also 273L. Thus, 273H/309S enhanced cell growth in spite of its p53-specific transactivation activity, while 273L suppressed cell growth in spite of its complete loss of the p53-specific transactivation. We concluded that the sequence-specific transactivation of p53 is not always correlated with its growth inhibitory activity.
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PMID:The 273rd codon mutants of p53 show growth modulation activities not correlated with p53-specific transactivation activity. 864 76

To characterize hepatocellular carcinoma (HCC) cells with mutant (m) p53 protein histologically, we examined 68 main nodules and 20 accessory lesions of 72 patients with HCC who underwent hepatic resection between October 1990 and September 1993. Some sections were fixed in periodate-lysine-paraformaldehyde, embedded in OCT compound, and stained with the mouse monoclonal antibody PAb1801 to m-p53 protein by the immunoperoxidase technique with avidin-biotin complexes. Other sections were fixed in 20% buffered formalin, embedded in paraffin, and stained with the mouse monoclonal antibody DO-1 to m-p53 protein in the same way. Lesions in which cells had nuclei stained for m-p53 protein were defined as being positive for the protein; 25 of the 68 main nodules and 14 of the 20 accessory lesions were positive. Large main nodules were more likely to be positive than small ones. Microscopic examination showed that a larger proportion of poorly differentiated main nodules than well differentiated nodules were positive. Larger proportions of main nodules with extracapsular invasion, septa, portal thrombi, or intrahepatic metastases were positive than main nodules without these features. Accessory lesions that seemed to be metastatic were almost all positive, but few accessory lesions that seemed to be of multicentric occurrence were positive. Our results suggest that lesions with m-p53 protein had a high grade of malignancy and metastasized readily.
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PMID:Characteristic histologic features of human hepatocellular carcinoma with mutant p53 protein. 866 20

Aberrations of the p53 and Rb tumour suppressor genes were examined in 12 human hepatocellular carcinoma (HCC)-derived cell lines from different geographic areas and 9 local HCCs by restriction fragment length polymorphisms (RFLP), polymerase chain reaction-single-strand conformation polymorphisms (PCR-SSCP) and DNA sequencing. The relationships between genetic changes and hepatitis B virus (HBV) DNA integration in samples were compared. None of the cell lines and tumours showed structural changes in the Rb gene, while 6 cell lines and 2 tumours had mutation or deletion in exons 5 to 8 of p53. Mutations include an AGG --> AGT (Arg --> Ser) transversion at codon 249 in PLC/PRF/5 and Mahlavu, an AAT --> AAA (Asn --> Cys) transversion at codon 200 in TONG/HCC, an AAG --> GAG (Lys --> Glu) transition at codon 139 in HCC-T, a CAT --> CGT (His --> Arg) transition at codon 214 in SC4, and a CCC --> CTC (Pro --> Leu) transition at codon 250 in SC8. In Huh4, an 18-bp deletion from codon 264 to 270 resulted in loss of Leu-Gly-Arg-Asn-Ser-Phe from the amino acid sequences 265 to 270, whereas Hep3B had a 7-kb deletion after exon 7 of p53. Our data indicate that whereas Rb may not have pleiotropic effects on HCC, p53 aberrations are frequently involved in hepatocarcinogenesis. Further, HBV infection appears to be unrelated to the micro-genetic changes of p53. The G to T codon-249-mutation is consistent with HCCs arising from areas at high risk for both aflatoxin B1 (AFB1) exposure and HBV infection.
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PMID:Tumour suppressor p53 and Rb genes in human hepatocellular carcinoma. 877 41

Although numerous studies have demonstrated increased expression of p53 protein in the Reed-Sternberg cells of Hodgkin's disease, little data exist as to whether mutations of the p53 gene is a common occurrence in this neoplasm. Using a microdissection technique coupled with PCR, single-strand conformation analysis, and DNA sequencing, we studied 23 cases of Hodgkin's disease for mutations within exons 5 to 8 of the p53 gene. We found seven mutations within six cases; six were missense mutations. An identical missense mutation was found in three cases (codon 243, methionine to isoleucine), and another identical missense mutation was found in an additional two cases (codon 204, glutamic acid to lysine). Verification of the mutations was accomplished either by direct Southern blotting of PCR-amplified p53 exon products from re-extracted DNA or by hybridization of cloned PCR-amplified p53 exon products from re-extracted DNA with a mutant-specific oligonucleotide. There was no good correlation between the presence of p53 mutations and the level of p53 protein expression, which was found to be overexpressed in all cases, the level of MDM2 protein expression, or the proliferation rate as determined by K-67 antibody. None of the cases with p53 mutation had evidence of Epstein-Barr virus within the Reed-Sternberg cells, as compared with 7 of 17 of the other cases (p < 0.06). These results suggest that p53 mutation may represent an important mechanism in the pathogenesis of Hodgkin's disease, and this mechanism may be independent of Epstein-Barr virus.
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PMID:p53 mutations in Hodgkin's disease. 887 83

Apoptosis induced in myeloid leukemic cells by wild-type p53 was suppressed by different cleavage-site directed protease inhibitors, which inhibit interleukin-1 beta-converting enzyme-like, granzyme B and cathepsins B and L proteases. Apoptosis was also suppressed by the serine and cysteine protease inhibitor N-tosyl-L-phenylalanine chloromethylketone (TPCK) [corrected], but not by other serine or cysteine protease inhibitors including N alpha-p-tosyl-L-lysine chloromethylketone (TLCK), E64, pepstatin A, or chymostatin. Protease inhibitors suppressed induction of apoptosis by gamma-irradiation and cycloheximide but not by doxorubicin, vincristine, or withdrawal of interleukin 3 from interleukin 3-dependent 32D non-malignant myeloid cells. Induction of apoptosis in normal thymocytes by gamma-irradiation or dexamethasone was also suppressed by the cleavage-site directed protease inhibitors, but in contrast to the myeloid leukemic cells apoptosis in thymocytes was suppressed by TLCK but not by TPCK. The results indicate that (i) inhibitors of interleukin-1 beta-converting enzyme-like proteases and some other protease inhibitors suppressed induction of apoptosis by wild-type p53 and certain p53-independent pathways of apoptosis; (ii) the protease inhibitors together with the cytokines interleukin 6 and interferon-gamma or the antioxidant butylated hydroxyanisole gave a cooperative protection against apoptosis; (iii) these protease inhibitors did not suppress induction of apoptosis by some cytotoxic agents or by viability-factor withdrawal from 32D cells, whereas these pathways of apoptosis were suppressed by cytokines; (iv) there are cell type differences in the proteases involved in apoptosis; and (v) there are multiple pathways leading to apoptosis that can be selectively induced and suppressed by different agents.
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PMID:Differential suppression by protease inhibitors and cytokines of apoptosis induced by wild-type p53 and cytotoxic agents. 890 12

A spatially well organized continuum of proliferation, differentiation, and death is displayed along crypt-villus units in the adult mouse small intestine. This continuum provides an opportunity to examine in vivo the mechanisms by which proliferative status changes as a function of cellular differentiation. Immunohistochemical studies of normal FVB/N mice revealed that as epithelial cells complete their terminal differentiation during a 48-72-h migration up villi, there is a marked and rapid fall in the levels of two important regulators of the G1/S transition, cyclin D1 and cyclin-dependent kinase (cdk) 2. However, cellular levels of their partners, cdk4 and cyclin E, remain unchanged as does the level of pRB. Adult FVB/N transgenic mice were studied that contained an intestinal fatty acid binding protein gene promoter (Fabpi) linked to wild type Simian virus 40 large T antigen (SV40 TAgWt) or a mutant TAg with Lys for Glu substitutions at residues 107 and 108 (SV40 TAgK107/8) that fails to bind pRB and related pocket proteins. Both transgenes are expressed only in villus enterocytes. SV40 TAgWt causes these terminally differentiated cells to re-enter the cycle. Re-entry is accompanied by a reduction in un/hypophosphorylated pRB, an induction of cyclin D1 and cdk2, but no change in cdk4, cyclin E, or E2F-1. In contrast, SV40 TAgK107/8 fails to induce re-entry and does not produce changes in un/hypophosphorylated pRB, cyclin D1, or cdk2 accumulation. These results suggest that un/hypophosphorylated pRB is an important mediator of the cell cycle arrest that normally occurs as enterocytes exit the crypt and complete their differentiation. Fabpi-directed expression of E2F-1 does not cause villus enterocytes to return to the cell cycle, alter their suppression of cyclin D1 or cdk2, or affect their state of differentiation, emphasizing the insensitivity of these cells to the effects of E2F-1. Analyses of p53(-/-) and p53(+/+) mice containing Fabpi-SV40 TAgWt and Fabpi-SV40 TAgK107/8 established that the proliferation induced by SV40 TAgWt does not require p53 and is associated with increased (p53-independent) apoptosis. The presence of cyclin E and cdk4 in differentiating villus enterocytes emphasizes that these cells retain part of their proliferative heritage expressed 24-72 h earlier in the crypt. The data suggest that down-regulation of cdk2 and/or cyclin D1 expression may be important for control of proliferative status and/or execution of terminal differentiation.
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PMID:Use of normal and transgenic mice to examine the relationship between terminal differentiation of intestinal epithelial cells and accumulation of their cell cycle regulators. 891 Apr 66

Cellular functions of tumor suppressor proteins can be mediated by protein-protein interactions. Using p53 as a probe to screen an expression library, a cDNA encoding a 250 kDa protein was isolated. Recombinant forms of this protein, designated PACT, bind to wild type p53 while two different mutations abolish this interaction. PACT protein can also interfere with p53 specific DNA binding. PACT contains a serine/arginine (SR) rich region and a C' terminal lysine rich domain. The 250 kDa PACT protein can be precipitated from cell lysates by a method specific for SR proteins. snRNPs can be co-immunoprecipitated from cells with anti-PACT antibodies. These antibodies stain cell nuclei in a speckled pattern reminiscent of the distribution of known splicing factors. Recently, RBQ1, a truncated human homologue of PACT was identified by virtue of Rb binding. We show that RBQ1 is truncated as a result of a possible mutational event. PACT can interact with both cellular Rb and p53.
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PMID:PACT: cloning and characterization of a cellular p53 binding protein that interacts with Rb. 901 Feb 16


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