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Regulation of NF-kB mediated transcription

Chris Phelps

Appointment Period: 2000-2001, Grant Year: [16]

Chris PhelpsThe NF-kB family of transcription factors are critical for eukaryotic growth and development and are key regulators of innate and adaptive immunity. NF-kB proteins are active as both homo- and heterodimers, which upon activation, bind with sequence specificity to DNA enhancer elements collectively known as kB sequences. Here they interact with a variety of other enhancer proteins and the basal transcriptional machinery to activate transcription. Prior to activation, NF-kB dimers are held inactive bymembers of the IkB (Inhibitors of kB) family of proteins. My work has focused on the interaction between NF-kB dimers and kB DNAsequences as well as the interaction of NF-kB and IkBa (the most common member of the IkB family). This work has shown that specific NF-kB dimmers show distinct specificity for different classes of kB DNA, indicating that he sequence of the kB DNA specifies binding by specific NF-kB factors. The binding to DNA is also highly cooperative, and the cooperativity is mediated by the dimerization domains of the NF-kB dimmers.

PUBLICATIONS (resulting from this training, and one recent one)

Phelps CB, Sengchanthalangsy LL, Malek S, Ghosh G. (2000) Mechanism of kappa B DNA binding by Rel/NF-kappa B dimers. J Biol Chem. 275:24392-9.

Phelps CB, Sengchanthalangsy LL, Huxford T, Ghosh G. (2000) Mechanism of I kappa B alpha binding to NF-kappa B dimers. J Biol Chem. 275:29840-6.

Huang D, Chen Y, Ruetsche M, Phelps CB, Ghosh G. (2001) X-Ray Crystal Structure of Proto-Oncogene Product c-Rel Bound to the CD28 Response Element of IL-2. Structure 9:669-78.

Huxford T, Mishler D, Phelps CB, Huang DB, Sengchanthalangsy LL, Reeves R, Hughes CA, Komives EA, Ghosh G. (2002) Solvent exposed non-contacting amino acids play a critical role in NF-kappaB/IkappaBalpha complex formation. J Mol Biol. 324:587-97.

Phelps CB, Ghosh G. (2004) Discreet mutations from c-Rel to v-Rel alter kappaB DNA recognition, IkappaBalpha binding, and dimerization: implications for v-Rel oncogenicity. Oncogene 23:1229-38.

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

Dawes-Hoang RE, Parmar KM, Christiansen AE, Phelps CB, Brand AH, Wieschaus EF. (2005) folded gastrulation, cell shape change and the control of myosin localization. Development. 132:4165-78.