p53-dependent downregulation of metastasis-associated laminin receptor.

Abstract

Based on observations suggesting a role for the tumor suppressor protein p53 in regulating expression of the 67-kDa laminin receptor precursor, 37LRP, we analysed the 37LRP promoter activity in a wild-type p53 (wt p53) ovarian carcinoma cell line and in a cisplatin-resistant subline with mutated p53. We observed an increased promoter activity in wt p53 cells as compared to the mutated-p53 line when the first intron of the 37LRP gene was present in the reporter construct. Cotransfection experiments showed that the promoter is downregulated by both wt and mutated p53. Deletion analysis of the first intron localized an enhancer activity in the first 5' 214 bp that upregulates both 37LRP and SV40 promoter activity and is repressed by both wt and mutant p53. Cotransfection, mutagenesis and gel-shift experiments identified a functional AP-2 cis-acting element in this intron region that is repressed by increased levels of both wt and mutated p53. Coimmunoprecipitation studies revealed AP-2 in physical association in vivo with both wt and mutated p53, indicating for the first time that interaction of p53 with AP-2 is involved in the repression mechanism and in the regulation of genes involved in cancer growth and progression.

• Authors: Michele Modugno, Elda Tagliabue, Elena Ardini, Valeria Berno, Enrico Galmozzi, Michele De Bortoli, Vincent Castronovo, Sylvie Ménard
• Journal: Oncogene (Oncogene) Vol. 21 Issue 49 Pg. 7478-87 (Oct 24 2002) ISSN: 0950-9232 [Print] England
• PMID: 12386810 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Primers
• Receptors, Laminin
• Tumor Suppressor Protein p53

Topics

• Base Sequence
• Blotting, Western
• DNA Primers
• Down-Regulation (physiology)
• Electrophoretic Mobility Shift Assay
• Female
• Flow Cytometry
• Fluorescent Antibody Technique, Indirect
• Humans
• Neoplasm Metastasis
• Ovarian Neoplasms (pathology, physiopathology)
• Precipitin Tests
• Receptors, Laminin (physiology)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (physiology)