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T Soussi

Publications and source records attributed to T Soussi.

At least 55 records · Page 3Linked to original sources
PubMed1999

Anti-apoptotic activity of p53 maps to the COOH-terminal domain and is retained in a highly oncogenic natural mutant.

The tumour suppressor p53 plays a complex role in the regulation of apoptosis. High levels of wild type p53 potentiate the apoptotic response, while physiological range, low levels of the protein have an anti-apoptotic activity in serum starved immortalized fibroblasts. Here we report that primary fibroblast-like cells that show normal growth control are also efficiently protected from apoptosis by the endogenous p53 activity. The capacity to inhibit apoptosis is not restricted to the wild type protein: the R-->H175 p53 mutant fully retains the anti-apoptotic activity of the wild type p53, providing a possible explanation for its high oncogenicity. Using a series of point and deletion mutants of p53 under the control of tetracycline-regulated promoter we show that certain mutants, like the wild type, protect cells at low levels but lead to apoptosis when overexpressed. This latter effect is lost upon deletion of a proline-rich domain in the NH2 part of the protein. The anti-apoptotic activity can be mapped to the extreme carboxy-terminal part of the protein and is therefore independent of other well characterized p53 activities. Our results add a new level of complexity to the network of interactions mediated by p53 in normal physiology and pathology.

Animals↗
PubMed1999

Functional analyses of a unique p53 germline mutant (Y236delta) associated with a familial brain tumor syndrome.

We have evaluated the functional properties of the unique p53 mutant Y236delta (deletion of codon 236) that gave rise to apparent cell-type specific tumor development. Four family members carrying this mutation in the germline developed early onset brain tumors, as previously reported. Deletion of residue Y236, which is tightly packed in an evolutionary conserved hydrophobic pocket, results in a protein with a mutant conformation according to immunoprecipitation with the conformation-sensitive antibodies PAb240 and PAb1620. The Y236delta mutant lacks specific DNA binding to the p53-responsive element in the WAF1-promoter, and functional analysis in Saos-2 cells revealed inability to transactivate the p53-responsive elements in the WAF1-promoter and the RGC sequence. The mutant has retained a functional oligomerization domain, a key element mediating the dominant negative effect, and inhibits DNA binding of wild-type p53. In addition, transactivation of endogenous wild-type p53 in LoVo cells was inhibited upon transfection of the mutant in a dose-dependent manner. Thus, in vitro and in vivo data suggest the loss of important tumor-suppressing functions and demonstrate a dominant negative effect of this unique p53 mutant that is associated with an unusual clustering of familial brain tumors.

Brain Neoplasms↗
PubMed1999

Mutant p53 proteins stimulate spontaneous and radiation-induced intrachromosomal homologous recombination independently of the alteration of the transactivation activity and of the G1 checkpoint.

We report here a systematic analysis of the effects of different p53 mutations on both spontaneous and radiation-stimulated homologous recombination in mouse L cells. In order to monitor different recombination pathways, we used both direct and inverted repeat recombination substrates. In each line bearing one of these substrates, we expressed p53 proteins mutated at positions: 175, 248 or 273. p53 mutations leading to an increased spontaneous recombination rate also stimulate radiation-induced recombination. The effect on recombination may be partially related to the conformation of the p53 protein. Moreover, p53 mutations act on recombination between direct repeats as well as between inverted repeats indicating that strand invasion mechanisms are stimulated. Although all of the p53 mutations affect the p53 transactivation activity measured on the WAF1 and MDM2 gene promoters, no correlation between the transactivation activity and the extent of homologous recombination can be drawn. Finally, some p53 mutations do not affect the G1 arrest after radiation but stimulate radiation-induced recombination. These results show that the role of p53 on transactivation and G1 cell cycle checkpoint is separable from its involvement in homologous recombination. A direct participation of p53 in the recombination mechanism itself is discussed.

Animals↗
PubMed1999

Anti-p53 antibodies are rarely detected in serum of patients with rheumatoid arthritis and Sjögren's syndrome.

OBJECTIVE: To detect evidence of abnormalities of the p53 protein in autoimmune diseases. Mutation of the p53 protein may inhibit apoptosis and thereby lead to cancer and possibly play a role in the pathogenesis of autoimmune diseases. METHODS: Serum antibodies to p53 are detected in 30 to 50% of patients with cancer who have p53 mutations. Using an ELISA, we determined the prevalence of anti-p53 antibodies in the serum of 106 patients with rheumatoid arthritis (RA), 72 patients with primary Sjögren's syndrome (SS), and 14 patients with lymphoma complicating SS. The presence of anti-p53 antibodies was also measured in the synovial fluid of 16 patients with RA. Positive sera by ELISA were confirmed by immunoprecipitation. RESULTS: Serum anti-p53 antibodies were detected in 2 of 106 patients with RA. The synovial fluid of one of these 2 patients was also studied and was positive. Anti-p53 antibodies were not detected in the other synovial fluids. Serum anti-p53 antibodies were not detected in 72 patients with primary SS alone, but were present in 2 of 14 patients with lymphoma complicating SS. CONCLUSION: Our results suggest that if p53 mutations have any role in the pathogenesis of some autoimmune diseases, they are rarely associated with the presence of anti-p53 antibodies in patients with RA. In patients with SS, the presence of serum anti-p53 antibodies might be an indirect sign of the development of a lymphoma.

Arthritis, Rheumatoid↗
PubMed1999

[Record no. 23: hMLH1].

Explore the source record for details and available documents.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Squamous cell carcinomas after allogeneic bone marrow transplantation for aplastic anemia: further evidence of a multistep process.

BACKGROUND: Secondary solid tumors are rare events occurring in patients who underwent allogeneic marrow transplantation for aplastic anemia and Fanconi's anemia. Human herpes virus 8 (HHV8), Epstein-Barr virus (EBV), and human papillomaviruses (HPV) sequences have been found in squamous cell carcinoma (SCC) occurring in organ transplant recipients. The tumor suppressor gene p53 has been strongly linked to the occurrence of SCC in the nonimmunocompromised population. PATIENTS AND METHODS: In eight patients with SCC, we searched for HHV8, EBV, varicella zoster virus, adenovirus, and HPV sequences from DNA extracted from selected areas of SCC. We also looked for p53 expression in those specimens as well as the presence of anti-p53 antibodies in the serum of these patients at the onset of SCC. RESULTS: In one patient, we found the presence of both HHV8 and EBV sequences, and in another patient we found HPV16 sequences. All five tumors that could be studied disclosed evidence of p53 accumulation, but none of the eight patients had anti-p53 antibodies in the sera. CONCLUSION: SCC developing in marrow transplant recipients seems to occur via a multistep process. Genetic predisposition may be present, as in patients with Fanconi's anemia. Transplantation-related factors, such as irradiation and chronic graft-versus-host disease, also have a role. In this article, we add two more potent risk factors: p53 alteration(s) and in some cases the presence of oncogenic viruses.

Anemia, Aplastic↗
PubMed1998

Regulation of the specific DNA binding activity of Xenopus laevis p53: evidence for conserved regulation through the carboxy-terminus of the protein.

Recombinant human p53 isolated either from E. coli or from insect cells is poorly active for binding to DNA but it can be dramatically stimulated by phosphorylation, antibody binding to the carboxy-terminal negative regulatory domain, short peptides derived from this negative regulatory domain or short single strands of DNA. We report here that Xenopus p53 has a very similar behavior. Using a new set of monoclonal antibodies directed either to the amino- or the carboxy-terminus of Xenopus p53, we demonstrate that the frog protein can be activated by specific carboxy-terminus monoclonal antibodies in order to bind to human p53 DNA response element. In addition, we report that such activation of both humans and frogs protein can also be achieved by small peptides derived from the carboxy-terminus of both p53. Although, the sequence of this region is not conserved in the various p53 species, the presence of conserved basic residues indicates that such activation is charge-dependent. This is confirmed by the finding that small poly-lysine peptides can activate both human and Xenopus p53. In vivo expression of Xenopus p53 indicates that this protein is able to transactivate a wide variety of human p53 response elements as long as the experiments are performed at 32 degrees C since activity at 37 degrees C, a temperature well above the natural temperature of Xenopus, is lost. Finally, we demonstrate that human mdm2 is able to down regulate the transcriptional activity of Xenopus p53.

Amino Acid Sequence↗