Date of Award

8-2000

Degree Name

Master of Science

Department

Biological Sciences

First Advisor

Dr. Bruce Bejcek

Second Advisor

Dr. Karim Essani

Third Advisor

Dr. John Geiser

Access Setting

Masters Thesis-Open Access

Abstract

The nuclear factor-КB (NF-КB)/Rel family of inducible dimeric transcription factors regulates numerous genes associated with the immune, mitogenic, and apoptotic responses. Investigations were made into the role of NF-КB in breast carcinoma (MCF-7, T47D, MDA-MB-231) and glioblastoma (U87MG, U373MG, Ul 18MG) cell lines. NF-КB binding to DNA was quantified using both gel mobility shift assays and transient transfections of a vector containing a luciferase gene under the control of 4 tandem copies of the NF-КB binding sequence. To determine the correlation between NF-КB activation, cellular proliferation, and foci formation, the tumor cells were cultured and analyzed in the presence of the NF-КB inhibitory compounds, prostaglandin A1 (PGA1) and acetylsalicylic acid (ASA). In addition, clones of dominant negative mutants which inhibit NF-КB activation were introduced into these tumor cell lines. One dominant negative mutant is a natural biological inhibitor of NF-КB, IКBα, modified so that it can no longer be phosphorylated and degraded. The other dominant negative mutant expressed a truncated form of p65, a monomer of the NF-КB complex. Breast carcinomas and glioblastomas showed elevated NF-КB activation when compared to normal breast epithelial cells. The tumor cells tested displayed reduced proliferation rates when subjected to NF-КB inhibition. Although, foci formation was reduced under the same inhibitory conditions this response was probably a direct result of decreased proliferation not cellular transformation. The investigations presented here demonstrate the involvement of NF-КB activation with proliferation of these cancer cell lines.

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