My thesis project focuses on the understanding of how inhibitor I-kappa-B and activator NF-kappa-B proteins mutually regulate each other by forming stable complexes. Although it is a well known fact that I-kappa-B inhibits NF-kappa-B from binding to DNA response elements, its role in sensitizing NF-kappa-B to inducible activation is less understood.

My project has two parts; first, to elucidate the mechanism of mutual regulation of I-kappa-B and NF-kappa-B using genetic and biochemical approaches and second, to investigate how different I-kappa-B proteins regulate NF-kappa-B dimers withspecificity using a structural approach.

The first part is being carried out in collaboration with Professor Alex Hoffmann and Elizabeth Komives. I have completed a substantial portion of the genetic and biochemical work which has allowed us to submit a manuscript for publication.

I have recently started the second part of my thesis project. My goal is to elucidate the structural characteristics of the I-kappa-B-alpha:p65 homodimer, I-kappa-B-beta:c-Rel homodimer and I-kappa-B-gamma:p50 homodimer complexes. These complexes are biologically significant and elucidation of their structures will provide a clear structural framework to understand the specificity in NF-kappa-B regulation.

I have all the relevant proteins in hand and has initiated crystallization trials. I have already obtained small crystals of some of these complexes, and my aim is to complete most of the proposed work within two years from now.

NF-kappa-B-I-kappa-B module has a profound role in pathogenesis including cancers. Several cancersincluding leukemia, lymphoma, beast and prostate cancers have been liked to abnormal activation of NF-kappa-B. Our collaborative approach to understand the basic biology of the I-kappa-B/NF-kappa-B complex will help combat these diseases.

PUBLICATIONS (resulting from this training)

Vaezeslami S, Mathes E, Vasileiou C, Borhan B, Geiger JH. The Structure of Apo-wild-type Cellular Retinoic Acid Binding Protein II at 1.4 A and its Relationship to Ligand Binding and Nuclear Translocation. J Mol Biol. 2006 Oct 27;363(3):687-701.

Mathes E, O'Dea E, Hoffmann A, Ghosh G. NF-kappa-B Dictates I-kappa-B Degradation Modes. 2008 (Submitted to Molecular Cell)