Candidate: Takeshi Shimamura

Degree of: Doctor of Philosophy

Department: Biological Sciences

Title: Roles and Regulation of NF-kB in Platelet-Derived Growth Factor Transformed Cells

Date: Thursday, August 1, 2002, 9:00 a.m. - 11:00 a.m.
1718 Wood Hall

Committee:
Dr. Bruce E. Bejcek, Chair
Dr. Alexander J. Enyedi
Dr. Bart O. Williams
Dr. Silvia Rossbach
Dr. John R. Geiser

Abstract:
Platelet Derived Growth Factor (PDGF) is overexpressed in various cancer cells and the overexpression is often correlated with its essential roles in both development and prognosis of several types of cancers.

Blinding of PDGF to its receptors induces receptor dimerization and subsequent auto-phosphorylation of tyrosine residues in the receptor's cytoplasmic domains. The phosphrylated tyrosine residues interact with the secondary signaling molecules to initiate signaling cascades that trigger cellular changes by affecting downstream effectors. 

In our recent publication, we have shown that a NF-kB mediates the transformation of mouse fibroblast cells overexpressing PDGF B chain. Though there is a significant correlation between PDGF stimulation and NF-dB activity, it is still unclear what secondary signaling molecules and downstream targets regulate NF-kB activity in the cell.

In glioblastoma U87-MG cells known to overexpress the PDGF B chain and the PDGF beta receptor, NF-kB activity is significantly increased. A dominant negative mutant of PDGF beta receptor missing five intracellular tyrosine residues, which is unable to activate multiple secondary signaling molecules significantly decreased NF-kB activity when it was introduced into U87-MG cells. When one of the five tyrosine residue is added back so that the dominant negative PDGF beta receptor can only activate PI3-K path way, NF-kB activity returned to the level that was normal to U87-MG glioblastoma cells.

In addition, treating U87-MG cells with chemical inhibitors of phosphatidylinocitol 3 kinase (PI3-K) pathway resulted in the significant inhibition of NF-kB activity in a dose dependent manner. The use of short interfering RNA (siRNA) against p110 kinase of PI3-K to suppress the expression of p110 kinase also resulted in the inhibition of PI3-K pathway activity and NF-KB activity.

The study presented here identifies that PI3-K pathway is one of the pathways that controls NF-kB activity in U87-MG glioblastoma cells. Elucidating the exact signaling cascades that mediate NF-kB activity upon PDGF stimulation will unveil the biology of PDGF induced transformation, which may lead to the discovery of novel molecular targets to suppress tumors with high PDGF activity.

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