Posttranscriptional regulation of p21WAF1/CIP1 expression in human breast carcinoma cells.
p21WAF1/CIP1 plays a major role in the induction of G1 arrest following DNA damage. Although p21WAF1/CIP1 expression is regulated by the tumor suppressor p53, induction of p21WAF1/CIP1 expression through p53-independent pathways has been described in numerous cell types. In this report, we describe the mechanism by which the retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induces p21WAF1/CIP1 in breast carcinoma cells possessing either a wild-type (MCF-7 cells) or mutated (MDA-MB-468 cells) p53. Exposure of MDA-MB-468 cells to this retinoid results in an approximately 10-fold increase in p21WAF1/CIP1 mRNA levels, whereas less than a 2-fold increase in p21WAF1/CIP1 gene transcription was observed as indicated by transient transfection experiments utilizing a p21WAF1/CIP1 promoter firefly luciferase reporter gene construct and nuclear run-off studies. We found similar results in the MCF-7 cells (Z-M. Shao et al., Oncogene, 11: 493-504, 1995). We have now found that while enhancing p21WAF1/CIP1 gene transcription minimally, this retinoid increases p21WAF1/CIP1 mRNA stability by 3-fold in both cell types. We also demonstrate that approximately 1.5 kb of the 3' untranslated region causes enhanced instability of p21WAF1/CIP1 mRNA. The retinoid-dependent increase in p21WAF1/CIP1 mRNA stability is accompanied by an increase in p21WAF1/CIP1 protein expression, as indicated by Western blot experiments utilizing anti-p21WAF1/CIP1 monoclonal antibody. This increase in p21WAF1/CIP1 is subsequently followed by the onset of programmed cell death in both cell types. Thus, CD437 is a novel retinoid which enhances p21WAF1/CIP1 mRNA levels through stabilization of the message regardless of the p53 status of the cell.
Department of Medicine, University of Maryland Cancer Center, Baltimore 21201, USA.
X S
XS
Li
A K
AK
Rishi
Z M
ZM
Shao
M I
MI
Dawson
L
L
Jong
B
B
Shroot
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U
Reichert
J
J
Ordonez
J A
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Fontana
D017209:Apoptosis; D001943:Breast Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis; D012176:Retinoids / Q000494:pharmacology; D014158:Transcription, Genetic
C099555:CD 437; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D012176:Retinoids