טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentShomer Inna
SubjectIsolation 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...
DepartmentDepartment of Medicine
Supervisor ? 18? Aaron Ciechanover
Full Thesis textFull thesis text - English Version


Abstract

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.