Dr. Arrigo De Benedetti's Research Focus

Major Research Interests:
Altered protein synthesis in solid tumors; gene expression; radioresistance by the protein kinase Tousled.

During the past few years, studies aimed at understanding the regulation and functions of the protein synthesis initiation factor eIF4E (cap-binding protein) in vivo, culminated in the unexpected finding that a moderate overexpression of this factor can result in dramatic phenotypic and proliferative changes, including malignant transformation. Moreover, we found that eIF4E is overexpressed in a variety of solid tumors. The potential clinical implications are being investigated. The principal goals of our work include: 1) To establish the feasibility of using antiserum against eIF4E as an aid to assess more accurately tumor-free margins in surgical resections and to distinguish pre-malignant lesions from cancerous, 2) To determine the chain of events and the components which, in response to increased eIF4E activity, mediate these alterations in growth regulation, proliferation, and differentiation, 3) Identification of some critical oncogene transcripts upregulated by eIF4E, 4) Identification of structural elements in these transcripts which make their translation so dependent on eIF4E, 5) Construction of a cDNA library of mRNAs that require excess eIF4E for translation. We then plan to use this library for the identification of novel potential oncogenes. 6) From this library we have recently cloned a translationally regulated protein kinase called Tousled. We subsequently found that Tousled specifically phosphorylates histone H3 and confers a high degree of resistance to radiation when overexpressed. This is likely due to chromatin remodeling and repair of damaged DNA.

Current Projects:

• DNA repair assays
• Gene Therapy
• Mutagenesis study of TLK1B
• Investigations of TLK1B substrates