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Understanding Free IkappaB-alpha Degradation.

Erika Mathes

Appointment Period: 2007-2008, Grant Years: [23]

Erika MathesIkappaB-alpha is the major inhibitor molecule of the transcription factor, NFkappaB, which is constitutively active in epithelial tumors, tumor cell lines, and lymphoid malignancies. NFkappaB activity is tightly regulated by IkappaB-alpha, therefore, understanding the regulation of this molecule is extremely important in the regulation of cancer. My work involved studying the different pathways that contribute to how much IkappaB-alpha is produced and degraded, resulting in the steady state level of the IkappaB-alpha protein. In the resting cell, IkappaB-alpha binds to NFkappaB in the cytoplasm, preventing it from entering the nucleus and activating gene transcription. When an extracellular stimulus encounters the cell, a signal cascade begins that modifies IkappaB-alpha and targets it for degradation. Once IkappaB-alpha is degraded, NFkappaB can enter the nucleus and activate transcription of its target genes.

This stimulus-dependent degradation pathway is very well characterized. I therefore studied an alternative pathway of degradation that does not require modifications or stimulation to degrade IkappaB-alpha. This degradation pathway is very important to maintain a constant flux of IkappaB-alpha protein, which allows for sufficient inhibition in the resting cell, and for efficient NFkappaB activation upon stimulation. I determined the regions of IkappaB-alpha that make the protein susceptible to this alternative pathway of degradation, and also determined the detrimental effects of NFkappaB activation when this pathway is altered. This pathway could potentially be used in order to dampen NFkappaB activation in cancerous cells that have elevated NFkappaB activation.

Truhlar SM, Mathes E, Cervantes CF, Ghosh G, Komives EA. Pre-folding IkappaBalpha alters control of NF-kappaB signaling. J Mol Biol. (2008) 380:67-82. PMID: 18511071; PMCID: PMC2519148.

Mathes E, O'Dea EL, Hoffmann A, Ghosh G. NF-kappaB dictates the degradation pathway of IkappaBalpha. EMBO J. (2008) 27:1357-67. PMID: 18401342; PMCID: PMC2374849.

Mathes E, Wang L, Komives E, Ghosh G. Flexible regions within IkappaBalpha create the ubiquitin-independent degradation signal. J Biol Chem. (2010) 285:32927-36. PMID: 20682784; PMCID: PMC2963393.

Understanding Free IkappaB-alpha Degradation.

 

IkappaB-alpha is the major inhibitor molecule of the transcription factor, NFkappaB, which is constitutively active in epithelial tumors, tumor cell lines, and lymphoid malignancies. NFkappaB activity is tightly regulated by IkappaB-alpha, therefore, understanding the regulation of this molecule is extremely important in the regulation of cancer. My work involved studying the different pathways that contribute to how much IkappaB-alpha is produced and degraded, resulting in the steady state level of the IkappaB-alpha protein. In the resting cell, IkappaB-alpha binds to NFkappaB in the cytoplasm, preventing it from entering the nucleus and activating gene transcription. When an extracellular stimulus encounters the cell, a signal cascade begins that modifies IkappaB-alpha and targets it for degradation. Once IkappaB-alpha is degraded, NFkappaB can enter the nucleus and activate transcription of its target genes.

 

This stimulus-dependent degradation pathway is very well characterized. I therefore studied an alternative pathway of degradation that does not require modifications or stimulation to degrade IkappaB-alpha. This degradation pathway is very important to maintain a constant flux of IkappaB-alpha protein, which allows for sufficient inhibition in the resting cell, and for efficient NFkappaB activation upon stimulation. I determined the regions of IkappaB-alpha that make the protein susceptible to this alternative pathway of degradation, and also determined the detrimental effects of NFkappaB activation when this pathway is altered. This pathway could potentially be used in order to dampen NFkappaB activation in cancerous cells that have elevated NFkappaB activation.

 

Truhlar SM, Mathes E, Cervantes CF, Ghosh G, Komives EA. Pre-folding IkappaBalpha alters control of NF-kappaB signaling. J Mol Biol. (2008) 380:67-82. PMID: 18511071; PMCID: PMC2519148.

 

Mathes E, O'Dea EL, Hoffmann A, Ghosh G. NF-kappaB dictates the degradation pathway of IkappaBalpha. EMBO J. (2008) 27:1357-67. PMID: 18401342; PMCID: PMC2374849.

 

Mathes E, Wang L, Komives E, Ghosh G. Flexible regions within IkappaBalpha create the ubiquitin-independent degradation signal. J Biol Chem. (2010) 285:32927-36. PMID: 20682784; PMCID: PMC2963393.