L. Margulies et Pb. Sehgal, MODULATION OF THE HUMAN INTERLEUKIN-6 PROMOTER (IL-6) AND TRANSCRIPTION FACTOR-C EBP BETA (NF-IL6) ACTIVITY BY P53 SPECIES/, The Journal of biological chemistry, 268(20), 1993, pp. 5096-5100
Constitutive up-regulation of interleukin-6 (IL-6) gene expression is
observed in many neoplastic cell lines. The contribution of mutations
in p53 to the up-regulation of the IL-6 promoter was evaluated in tran
sient transfection experiments. In HeLa cells, wild-type (wt) human or
murine p53 preferentially repressed the IL-6 promoter. The p53 mutant
s Val-135 and Phe-132 up-regulated IL-6 promoter activity in these cel
ls at both 32.5 and 37-degrees-C. The temperature-sensitive Val-135 mu
tant was not only not inhibitory or ''wt-like'' at the lower temperatu
re, but had gained a transcriptional activator phenotype which was tem
perature-independent in HeLa cells. The functional DNA target for tran
scriptional modulation of the IL-6 promoter by p53 species included th
e multiple cytokine- and second messenger-response element (-173 to -1
45); point mutations in the transcription factor C/EBPbeta-binding sit
e within the second messenger-response element largely blocked the abi
lity of p53 mutants Val-135 and Phe-132 to up-regulate this promoter.
The up-regulation of IL-6 promoter constructs by co-transfection into
HeLa cells of a C/EBPbeta constitutive expression vector was blocked i
n a dominant negative manner by wt p53. In contrast, the p53 mutants V
al-135 and Phe-132 further enhanced C/EBPbeta-mediated up-regulation o
f IL-6 promoter constructs. The modulation of C/EBPbeta function by p5
3 species provides a basis for the involvement of p53 not only in the
regulation of cytokine synthesis but also in the altered responsivenes
s of tumor cells to cytokines.