Estradiol induces functional inactivation of p53 by intracellular redistribution.
Estrogen treatment of MCF-7 cells grown in serum-free medium induced a modification of the intracellular distribution of p53 protein. Western blot analysis and immunofluorescence staining showed that p53 was localized in the nucleus of untreated cell and that after 48 h of hormone treatment, it was mostly localized in the cytoplasm. This effect was blocked by the antiestrogen ICI182,780. Intracellular redistribution of p53 was correlated to a reduced expression of the WAF1/CIP1 gene product and to the presence of degradation fragments of p53 in the cytosol. Estradiol treatment prevented the growth inhibition induced by oligonucleotide transfection, simulating DNA damage. This observation indicated that the wild-type p53 gene product present in the MCF-7 cell could be inactivated by estradiol through nuclear exclusion to permit the cyclin-dependent phosphorylation events leading to the G1-S transition. In addition, the estradiol-induced inactivation of p53 could be involved in the tumorigenesis of estrogen-dependent neoplasm.
Molinari
A M
AM
Istituto di Patologia Generale ed Oncologia, Facoltà di Medicina e Chirurgia, Seconda Università degli Studi di Napoli, Naples, Italy.
Bontempo
P
P
Schiavone
E M
EM
Tortora
V
V
Verdicchio
M A
MA
Napolitano
M
M
Nola
E
E
Moncharmont
B
B
Medici
N
N
Nigro
V
V
Armetta
I
I
Abbondanza
C
C
Puca
G A
GA
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004249:DNA Damage; D004591:Electrophoresis, Polyacrylamide Gel; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D016193:G1 Phase; D006801:Humans; D007150:Immunohistochemistry; D016196:S Phase; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004965:Estrogen Antagonists; D016159:Tumor Suppressor Protein p53; D000077267:Fulvestrant; D004958:Estradiol