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The Nuclear Factor kappaB (NF−κB) family
of induced transcription factor proteins plays a vital role in the
immune response of higher organisms. Though NF−κB is a well-known
transcription activator it also functions as a transcription repressor
for many genes. The mechanism of transcription activation of such
NF−κB-repressed genes remains poorly understood, which we intend to
address through this proposal. We hypothesize that ‘subtle changes in
specific NF−κB dimer stability on κB-DNA site of the promoter/enhancer
region of NF−κB-repressed genes decide their transcriptional outcome’. NF-kappaB (NF−κΒ) refers to a family of
proteins, which regulate the expression of a large number of genes
important for human health. In normal cells, NF−κΒ activity is
regulated. Activated NF−κΒ migrates to the nucleus and binds to its DNA
recognition sites and regulates its target gene transcription.
Abnormally high NF−κΒ activity has been recognized as a critical factor
in cancer and inflammatory diseases. This makes NF−κΒ an important drug
target in the malignant cells. The NF−κΒ family is comprised of five
members, namely, p50, p52, RelA, RelB and c-rel. The family members form
dimers in various combinations amongst themselves with RelA:p50
heterodimer being the most abundant followed by p50 homodimer; the other
dimers either exist at very low concentrations physiologically and in
some cases are not observed experimentally. The sequence of the κB DNA on the
promoter/enhancer site of a target gene plays a major role in the
preferential binding of certain NF−κB dimers. Bcl3 (B cell lymphoma 3) protein has an
emerging role in a number of autoimmune pathologies and different
cancers. It is identified as a proto-oncogene with a central role in
regulating NF-kappaB signaling. Belonging to the IkappaB family of
proteins, which is known for its inhibitory role of the NF-kappaB
pathway, Bcl3 plays a dual role in transcription activation as well as
repression of NF-kappaB target genes. It accomplishes its role as a
transcription regulator by interacting with p50 and p52 subunits of
NF-kappaB in their homodimer form. Though the interaction of Bcl3 with
p50 and p52 homodimers is well-established the details of the
interaction active site of the proteins required for designing any
potential drug target remains elusive. This is despite the fact that
3-dimensional crystal structures of the individual components of the
Bcl3-p50/p52 complex, namely, Bcl3, p50 homodimer, and p52 homodimer are
now available for over a decade. Molecular Mechanism of transcription activation of genes repressed by NFkappaB:
Here
my lab is working ‘to study the mechanism of transcription activation
of NF−κB-repressed Interferon Regulatory factor (IRF) target genes. The
research outcome will provide insights for engineering ways to regulate
the transcription of specific genes that get deregulated in diseased
cells.Understanding NF-kappaB dimer dynamics in NF-kappaB driven transcription :
My lab is working
towards understanding the formation and stabilization of different NF−κΒ
dimers using various biophysical and molecular biology techniques.Understanding Gene Regulation and Targeting protein-protein Interactions in a proto-oncogene System:
My lab is working to study this interaction using various biophysical techniques.
