Xs. Li et al., POSTTRANSCRIPTIONAL REGULATION OF P21(WAF1 CIP1) EXPRESSION IN HUMAN BREAST-CARCINOMA CELLS/, Cancer research, 56(21), 1996, pp. 5055-5062
p21(WAF1/CIP1) plays a major role in the induction of G(1) arrest foll
owing DNA damage. Although p21(WAF1/CIP1) expression is regulated by t
he tumor suppressor p53, induction of p21(WAF1/CIP1) expression throug
h 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) in
duces p21(WAF1/CIP1) in breast carcinoma cells possessing either a wil
d-type (MCP-7 cells) or mutated (MDA-MB-468 cells) p53. Exposure of MD
A-MB-468 cells to this retinoid results in an approximately 10-fold in
crease in p21(WAF1/CIP1) mRNA levels, whereas less than a 2-fold incre
ase in p21(WAF1/CIP1) gene transcription was observed as indicated by
transient transfection experiments utilizing a p21(WAF1/CIP1) promoter
firefly luciferase reporter gene construct and nuclear run-off studie
s. We found similar results in the MCF-7 cells (Z-M. Shao et al., Onco
gene, 11: 493-504, 1995), We have now found that while enhancing p21(W
AF1/CIP1) gene transcription minimally, this retinoid increases p21(WA
F1/CIP1) mRNA stability by 3-fold in both cell types. We also demonstr
ate that similar to 1.5 kb of the 3' untranslated region causes enhanc
ed instability of p21(WAF1/CIP1) mRNA. The retinoid-dependent increase
in p21(WAF1/CIP1) mRNA stability is accompanied by an increase in p21
(WAF1/CIP1) protein expression, as indicated by Western blot experimen
ts utilizing anti-p21(WAF1/CIP1) monoclonal antibody. This increase in
p21(WAF1/CIP1) is subsequently followed by the onset of programmed ce
ll death in both cell types. Thus, CD437 is a novel retinoid which enh
ances p21(WAF1/CIP1) mRNA levels through stabilization of the message
regardless of the p53 status of the cell.