Tumor-derived p53 mutants induce NF-kappaB2 gene expression.
Overexpression of mutant p53 is a common theme in tumors, suggesting a selective pressure for p53 mutation in cancer development and progression. To determine how mutant p53 expression may lead to survival advantage in human cancer cells, we generated stable cell lines expressing p53 mutants p53-R175H, -R273H, and -D281G by use of p53-null human H1299 (lung carcinoma) cells. Compared to vector-transfected cells, H1299 cells expressing mutant p53 showed a survival advantage when treated with etoposide, a common chemotherapeutic agent; however, cells expressing the transactivation-deficient triple mutant p53-D281G (L22Q/W23S) had significantly lower resistance to etoposide. Gene expression profiling of cells expressing transcriptionally active mutant p53 proteins revealed the striking pattern that all three p53 mutants induced expression of approximately 100 genes involved in cell growth, survival, and adhesion. The gene NF-kappaB2 is a prominent member of this group, whose overexpression in H1299 cells also leads to chemoresistance. Treatment of H1299 cells expressing p53-R175H with small interfering RNA specific for NF-kappaB2 made these cells more sensitive to etoposide. We have also observed activation of the NF-kappaB2 pathway in mutant p53-expressing cells. Thus, one possible pathway through which mutants of p53 may induce loss of drug sensitivity is via the NF-kappaB2 pathway.
Scian
Mariano J
MJ
Department of Biochemistry and Massey Cancer Center, Virginia Commonwealth University, P.O. Box 980614, Richmond, Virginia 23298, USA.
Stagliano
Katherine E R
KE
Anderson
Michelle A E
MA
Hassan
Sajida
S
Bowman
Melissa
M
Miles
Mike F
MF
Deb
Swati Palit
SP
Deb
Sumitra
S
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D005047:Etoposide / Q000494:pharmacology; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
D018076:DNA, Complementary; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D012313:RNA; D005047:Etoposide; D001973:Bromodeoxyuridine