|Ph.D Student||Shomer Inna|
|Subject||Isolation and Characterization of the Ubiquitin Ligase|
Involved in the Processing of P105 NF-kB Precursor
to the P50 Active Subunit: Analysis of
Mechanisms of Action and...
|Department||Department of Medicine||Supervisor||? 18? Aaron Ciechanover|
|Full Thesis text|
NF-κB is a key transcriptional regulator involved in inflammation and cell
proliferation, survival, and transformation. It was shown to be the central
element to link between chronic inflammation and malignant transformation.
p105 precursor of NF-κB that can be either completely degraded or partially
processed to produce the p50 active subunit. Several key steps in its
activation are mediated by the ubiquitin (Ub) system. One uncharacterized
step is limited proteasomal processing of the NF-κB1 precursor p105 to the
p50 active subunit. Here we identify KPC1 as the ubiquitin ligase (E3) that
mediates p105 processing both under basal conditions and following
signaling. The C-terminal ankyrin repeats of p105 are necessary for its
interaction with KPC1 and for its subsequent ubiquitination and processing.
Overexpression of KPC1 promotes inhibition of tumor growth mediated
probably via excessive generation of p50. Interestingly, excessive
p50 down regulates p65, explaining the possible lack of the ‘canonical’,
p50•p65 tumor promoting NF-κB. Transcript analysis of KPC1 overexpressing
tumors reveals increased expression of genes associated with tumor
suppressive signals. Functional analysis suggested a re-establishment of
“social” micro-environmental interactions in the p50 and KPC1-
overexpressing tumors. Overall, KPC1 regulation of NF-κB1 processing
appears to constitute an important balancing step among the stimulatory and
inhibitory activities of the transcription factor in cell growth control.