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Estrogen Up-Regulation of p53 Gene Expression in MCF-7 Breast Cancer Cells Is Mediated by Calmodulin Kinase IV-Dependent Activation of a Nuclear Factor B/CCAAT-Binding Transcription Factor-1 Complex

Department of Veterinary Physiology & Pharmacology (C.Q., T.N., J.S., I.S., R.S.) and Department of Veterinary Anatomy and Public Health (R.B.), Texas A&M University, College Station, Texas 77843-4466

Address all correspondence and requests for reprints to: Stephen H. Safe, Department of Veterinary Physiology & Pharmacology, Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466. E-mail: ssafe{at}cvm.tamu.edu.

This study investigates the mechanism of hormonal regulation of p53 gene expression in MCF-7 human breast cancer cells. 17ß-Estradiol (E2) induced a 2-fold increase in p53 mRNA levels and a 2- to 3-fold increase in p53 protein. Analysis of the p53 gene promoter has identified a minimal E2-responsive region at -106 to -40, and mutation/deletion analysis of the promoter showed that motifs that bind CCAAT-binding transcription factor-1 (CTF-1) and nuclear factor B (NFB) proteins are required for hormone responsiveness. The p65 subunit of NFB was identified in both nuclear and cytosolic fractions of untreated MCF-7 cells; however, formation of the nuclear NFB complex was E2 independent. Hormonal activation of constructs containing p53 promoter inserts (-106 to -40) and the GAL4-p65 fusion proteins was inhibited by the intracellular Ca²⁺ ion chelator EGTA-AM and Ca²⁺/calmodulin-dependent protein kinase (CaMK) inhibitor KN-93. Constitutively active CaMKIV but not CaMKI activated p65, and treatment of MCF-7 cells with E2 induced phosphorylation of CaMKIV but not CaMKI. The results indicate that hormonal activation of p53 though nongenomic pathways was CaMKIV-dependent and involved cooperative p65-CTF-1 interactions.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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