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The Role of RelB in the Regulation of p100 Processing and DNA Binding by p52 in Cancer

Amanda Fusco

Appointment Period: 2006-2007, Grant Years: [22]

Amanda FuscoThe dimeric NF-KB transcription factors are formed from five family members, p50 (NFKBI), ReIA (p65), p52 (NF-KB2), c-Rel, and RelB. p50 and p52 are the processed products of precursor proteins, p105 and p100, respectively. RelA homo-and heterodimer are activated through classical NF-KB signaling pathways that are linked to IKKbeta activation. These dimers are responsible for rapid activation of genes that are important for inflammation and immune response. RelB/p52 are generated from the inactive p100/RelB complex through non-classical NF-KB signaling pathways, which involve IKKalpha activation. The RelB/p52 heterodimer is known to be important for organogenesis and cell survival. Aberrant processing of p100 into p52 is seen in a large number of cancers

I have been working on two related projects; first, determination of NF-KB dimer specificity for target DNA sequences, and second, investigation of the role of RelB in p100 processing/degradation. The first project has two components: To determine affinities of different NFKB dimers for KB DNA sequences and to determine the X-ray crystal structure of RelB/p52 heterodimer. I have found that whereas RelA dimers can discriminate target DNAs, the RelB/p52 heterodimer binds to all KB DNAs with similar affinities tested so far. I have grown crystals of RelB/p52/DNA complex that diffract to 3.0Å resolution, and I am in the process of completing the structure. We hope that the structure might explain as to why RelB/p52 is more promiscuous in DNA binding than the RelA dimers. In my second project, I have shown that RelB protects p100 from degradation and processing in resting cells. I have further shown that dimerization of p100 with RelB is absolutely essential for this protective function.

Huang DB, Phelps CB, Fusco AJ, Ghosh G. Crystal structure of a free kappaB DNA: insights into DNA recognition by transcription factor NF-kappaB. J Mol Biol. (2005) 346:147-60. PMID: 15663934.

Fusco AJ, Savinova OV, Talwar R, Kearns JD, Hoffmann A, Ghosh G. Stabilization of RelB requires multidomain interactions with p100/p52. J Biol Chem. (2008) 283:12324-32. PMID: 18321863; PMCID: PMC2431000.

Fusco AJ, Huang DB, Miller D, Wang VY, Vu D, Ghosh G. NF-kappaB p52:RelB heterodimer recognizes two classes of kappaB sites with two distinct modes. EMBO Rep. (2009) 10:152-9. PMID: 19098713; PMCID: PMC2637311.