One of the major reasons that we are seeking at a new markers for cancers, is because mechanism cancer cell death have a much poorer understandings in the absence of functional p53. In response to genotoxic stress, p53 controls a broad range of cellular responses such as cell cycle arrest or apoptosis. p53 tumor suppressor is mutated in approximately 50% of many different cancer cells and normally they are resistance to therapy.
Therefore, one would expect that wtp53 cancer cells should be more sensitive to conventional treatment, but, in the true reality, wtp53 cancer cells exhibit extreme resistance to radio- or chemotherapy. The TP53 mutations are rare in certain human cancer entities (e.g., melanoma, colon cancer, glioblastoma multiforme and others cancers). Therefore, that can support the notion that wtp53 activity in cancer may not always be a beneficial factor in preventing tumor progression. On the other hand, wtp53 may contribute to overall survival potential and thus counteract cytotoxic effects of tumor therapies targeting DNA damage pathways.

Our group is interested in evaluating in wtp53 cancer cells:

1) Post-translational modifications on p53 with special focus on phosphorylation and acetylation sites.

2) p53-DNA-binding activity upon different DNA damaging agents.

3) Transcriptional activity of p53.

4) The resistance/sensitivity to the chemotherapy.

5) Apoptosis pathways.

***Large number of molecular and cellular techniques will be used in this project***.

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Dr Hajji Nabil

Lecturer in Toxicology

Imperial College London

Hammersmith Campus

DuCane Road London

W12 0NN UK

Tel: +44-20-7...

Fax: +44-20-759-47393

email: n.hajji@imperial.ac.uk

Epigenetic alterations, biomarkers and disease risk

During the last decade one of the fastest advancing areas of research in toxicological sciences is the study of epigenetic pathways that are involved in chemical-induced diseases. Identification of new potential biomarkers at the early phases of tumorogenesis is considered as important tools for disease progression diagnostic and preventive treatment designs. Post-translational modifications of histone tail has emerged as frequent modifications that often occur in tumorigenesis and that play an important role in tumor development, progression, and resistance to the conventional treatment.
Our group investigates post-translational modifications of histone tail as possible epigenetic code (Fig1), attempting to put together a comprehensive picture of the overall process of resistance/sensitivity to the chemicals and to evaluate the significance of cause and effect relationships between environmental (toxicants) factors and disease endpoints.



Growing experimental evidence suggests that neoplastic transformation, characterized by altered patterns of cell death, does not necessarily destroy the potential that cells have to undergo apoptosis under appropriate environmental conditions. Various chemical agents can restore this potential, and these possibilities are currently being exploited in attempts to develop anticancer therapies using such agents. Among the most effective of these are histone deacetylase (HDAC) inhibitors. Histone acetylation and deacetylation play important roles in the modulation of chromatin topology and the regulation of gene transcription. HDAC inhibition induces the accumulation of hyperacetylated nucleosome core histones in most regions of chromatin but affects the expression of only a small subset of genes, leading to transcriptional activation of some genes, but repression of an equal or larger number of other genes (Fig2).
Our aim as well is to investigate in the model of multidrug-resistance cell lines the effect of HDACs inhibition on activation and/or efficiency of the different apoptotic signaling pathways (Fig3).










Fellowship postdoctoral: 2005-2007: Epigenetic: «Epigenetic control of programmed cell death in lung carcinoma cells resistant to conventional anticancer treatments». Financing Entity: Karolinska institutet, Stockholm, Sweden.

Fellowship postdoctoral:2005-2007: Epigenetic: «Possible neuroprotection role of histone deasetyase inhibitors class I in the inflammation-mediated model of Parkinson Diseases». Financing Entities: University of Seville, Spain. and Karolinska institutet, Stockholm, Sweden.

Fellowship postdoctoral: 2004-2005: Epigenetic: «Possible role of histone deacetylases (HDACs), in skewed gene expression in RIN-m5F line cells model». Financing Entity: University of Seville, Spain.

Fellowship pre-doctoral: 2002-2003: Ecotoxicology: « los embalses de Arrocampo y Torrejón ». Financing Entity: A.I.E. Nuclear Centre Almaraz-Trillo, Extremadura, Spain.

Fellowship pre-doctoral: 1999-2003: Ecotoxicology: «the Aznalcóllar mine harmful effects on storks». Financing Entities: Junta de Andalucia , Biology Station of Doñana (CSIC) and Department of Cell Biology of Seville. Faculty of Biology. University of Seville.

Fellowship pre-doctoral: 1999-2004: Oncology: «Characterization of catalytic inhibitors of DNA topoisomerase II: DNA damage modulation by ionizing radiation». Financing Entity: Junta de Andalucia.