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| Posttranscriptional regulation of p21(WAF1/CIP1) expression in human breast carcinoma cells |
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| Author(s): Li XS, Rishi AK, Shao ZM, Dawson MI, Jong L, Shroot B, Reichert U, Ordonez J, Fontana JA |
| Source: CANCER RESEARCH Volume: 56 Issue: 21 Pages: 5055-5062 Published: NOV 1 1996 |
| Times Cited: 84 References: 56 |
| Abstract: p21(WAF1/CIP1) plays a major role in the induction of G(1) arrest following DNA damage. Although p21(WAF1/CIP1) expression is regulated by the tumor suppressor p53, induction of p21(WAF1/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 p21(WAF1/CIP1) in breast carcinoma cells possessing either a wild-type (MCP-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 p21(WAF1/CIP1) mRNA levels, whereas less than a 2-fold increase 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 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 p21(WAF1/CIP1) gene transcription minimally, this retinoid increases p21(WAF1/CIP1) mRNA stability by 3-fold in both cell types. We also demonstrate that similar to 1.5 kb of the 3' untranslated region causes enhanced 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 experiments utilizing anti-p21(WAF1/CIP1) monoclonal antibody. This increase in p21(WAF1/CIP1) is subsequently followed by the onset of programmed cell death in both cell types. Thus, CD437 is a novel retinoid which enhances p21(WAF1/CIP1) mRNA levels through stabilization of the message regardless of the p53 status of the cell. |
| Document Type: Article |
| Language: English |
Addresses:
1. UNIV MARYLAND, CTR CANC, DEPT MED, DIV HEMATOL & MED ONCOL, BALTIMORE, MD 21201 USA
2. UNIV MARYLAND, CTR CANC, DEPT PATHOL, BALTIMORE, MD 21201 USA
3. VET AFFAIRS MED CTR, BALTIMORE, MD 21201 USA
4. SRI INT, DIV LIFE SCI, MENLO PK, CA 94025 USA
5. CTR INT RECH DERMATOL GALDERMA, F-06902 VALBONNE, FRANCE |
| Publisher: AMER ASSOC CANCER RESEARCH, 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA |
| Subject Category: Oncology |
| IDS Number: VP486 |
| ISSN: 0008-5472 |
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