Biomedical subjects

Sonia Lain

Publications and source records attributed to Sonia Lain.

4 recordsLinked to original sources

PubMed2005

Pilot screening programme for small molecule activators of p53.

Activation of the p53 tumour suppressor is predicted to have therapeutically beneficial effects. Many current anti-cancer therapies activate the p53 response via DNA damage. Non-genotoxic activation of the p53 pathway would open the way to long-term and possibly prophylactic treatments. We have established a simple protocol to screen small compound libraries for activators of p53-dependent transcription, and to select and characterise the most interesting hits, which include non-genotoxic activators. These compounds or their derivatives are of potential clinical interest. This approach may also lead to the identification of novel p53-activating compound families and possibly to the description of novel molecular pathways regulating p53 activity.

Animals↗

PubMed2003

Differences in the ubiquitination of p53 by Mdm2 and the HPV protein E6.

The human papillomavirus (HPV) protein E6 can promote the ubiquitination of the p53 tumour suppressor in vitro, providing an explanation for the ability of E6 to induce p53 degradation in vivo and contribute to the potential tumorigenic effect of the virus. Instead, in non-infected cells, p53 levels are primarily destabilised by the ubiquitin E3 ligase activity of the Mdm2 protein. Here we have compared the effects of E6 and Mdm2 on p53 ubiquitination in vivo. We show that whereas in the presence of Mdm2 proteasome inhibitors induce the accumulation of ubiquitinated forms of p53, this does not occur in the presence of E6. Accordingly, we confirm that the effect of E6 and p53 is independent of the six C-terminal lysine residues in p53, which have previously been described to play an important role for effective ubiquitination and degradation of 53 mediated by Mdm2. We also show that other yet unidentified residues in p53 are also susceptible to ubiquitination. These results indicate that E6 does not induce ubiquitination of p53 in the same way as Mdm2 in order to promote its degradation, suggesting important differences between the Mdm2 and E6 effects on p53 degradation.

Amino Acids↗

PubMed2003

Oligomerization of the human ARF tumor suppressor and its response to oxidative stress.

The tumor suppressor ARF plays an important role as an inhibitor of the Mdm2-mediated degradation of p53. Here we demonstrate that human ARF (p14ARF) can form homo-oligomers. The stability of the oligomers is favored by oxidizing agents in a reversible fashion and involves all three cysteine residues in p14ARF. Furthermore, the effect of p14ARF in clonogenic assays is moderately but reproducibly increased by the mutation of its cysteine residues. We also observed that altering the amino terminus of p14ARF resulted in the appearance of remarkably stable oligomers. This indicates that the amino terminus of p14ARF interferes with the ability of the protein to form multimeric complexes. These observations suggest that p14ARF activity may be linked to its oligomerization status and sensitive to the redox status of the cell.

Amino Acid Sequence↗

PubMed2002

Therapeutic exploitation of the p53 pathway.

Analysis of the gene encoding p53 could serve to evaluate the effectiveness of a cancer treatment. Mutations in this gene occur in half of all human cancers, and regulation of the protein is defective in a variety of others. Novel strategies that exploit our knowledge of the function and regulation of p53 are being actively investigated. Strategies directed at treating tumours that have p53 mutations include gene therapy, viruses that only replicate in p53 deficient cells, and the search for small molecules that reactivate mutant p53. Potentiating the function of p53 in a non-genotoxic way in tumours that express wildtype protein can be achieved by inhibiting the expression and function of Mdm2 or viral oncoproteins.

Adenoviridae↗