Wolf, Dieter A.; Schulz, Peter; Fittler, Friedrich
(1992):
Transcriptional regulation of prostate kallikrein-like genes by androgen.
In: Molecular Endocrinology, Vol. 6, No. 5: pp. 753-762
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Abstract
Using gene-specific synthetic oligonucleotides the
expression and regulation of kallikrein-like genes in
the human prostatic cancer cell line LNCaP were
studied. Prostate-specific antigen (PSA) and human
glandular kallikrein (hGK-1) together constitute a
subfamily of serine proteases exclusively produced
in the human prostate. RNA analysis revealed that
both genes are expressed in LNCaP cells with PSA
basal levels being 2-fold higher than hGK-1 levels.
Both mRNAs are induced over a period of 24 h in
the presence of 3.3 nM of the synthetic androgen
mibolerone. Stimulation of PSA RNA is about 5-
fold,whereas hGK-1 stimulation is less pronounced.
Nuclear run-on analysis revealed that androgen induction
of kallikrein-like genes in LNCaP cells is a
rapid event (c3 h) occurring at the level of transcription
initiation. Treatment of cells with cycloheximide
demonstrates that, while PSA/hGK-1 basal transcription
strictly depends on continuous protein synthesis,
transcriptional induction by androgen does
not. This suggests the direct involvement of the
androgen receptor in the induction process independent
of additional labile protein factors necessary
for kallikrein basal transcription. A binding motif
is present in the PSA and hGK-1 promoters, closely
resembling the consensus sequence for steroidresponsive
elements. The androgen antagonist cyproterone
acetate was also able to stimulate transcription
of kallikrein-like genes in LNCaP cells. In
contrast, androgen-dependent transcriptional
suppression of the protooncogene c-myc was
strongly counteracted by cyproterone acetate. Thus,
antiandrogens act differentially on androgen-regulated
prostate-specific (PSA, hGK-1) and growthrelated
(c-myc) gene expression in LNCaP cells.