Nucleic Acids Research, Vol 27, Issue 15 3111-3119, Copyright © 1999 by Oxford University Press
AK Rishi, RJ Sun, Y Gao, CK Hsu, TM Gerald, MS Sheikh, MI Dawson, U Reichert, B Shroot, AJ Jr, G Brewer and JA Fontana
The biologically active synthetic retinoid CD437 (6-[3-adamantyl-4-
hydroxyphenyl]-2-naphthalene, AHPN) and different human breast carcinoma
(HBC) cell lines were used to examine the possible mechanism(s) of gadd45
induction. Northern blot analysis of mRNA isolated from MCF-7, MDA-MB-468
and MDA-MB-231 HBC cell lines demonstrated a progressive increase in the
1.4 kb gadd45 transcript after exposure to 1 microM CD437. Western blot
analysis showed increased gadd45 protein levels in MDA-MB-468 HBC cells
following exposure to CD437. CD437 increased gadd45 mRNA levels by
approximately 20-fold in MDA-MB-468 cells, however, the transcriptional
activity was increased approximately 2-3-fold as demonstrated by the human
gadd45 promoter-luciferase reporter construct and nuclear run-off assays.
Sublines of MDA-MB-468 HBC cells expressing stably integrated GADD45 cDNA
fragments were obtained and CD437-dependent induction of GADD45 analyzed.
We report that approximately 300 nt located in the 5"- untranslated region
(5"-UTR) of gadd45 mRNA are involved in the CD437- dependent 4-fold
enhanced stability of gadd45 transcripts. MDA-MB-468 cells were stably
transfected with either a plasmid having a CMV promoter-driven rabbit
beta-globin gene or plasmids having a CMV promoter-driven chimeric gadd45
5"-UTR-rabbit beta-globin gene, where the entire gadd45 5"-UTR (from +1 to
+298) or a 45 bp subfragment of the gadd45 5"-UTR (from +10 to +55) was
positioned at the 5"-end of the rabbit beta-globin gene. CD437 was found to
up-regulate expression of both the chimeric gadd45 -rabbit beta-globin
transcripts, suggesting that cis element(s) involved in the CD437-dependent
enhanced stability of gadd45 mRNA are contained in the 45 nt of the 5"-UTR
of the gadd45 mRNA.
ARTICLES
Post-transcriptional regulation of the DNA damage-inducible gadd45 gene in human breast carcinoma cells exposed to a novel retinoid CD437
Department of Internal Medicine and Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA, rishia@karmanos.org
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