Mitogen-activated protein kinase is involved in the degradation of p53 protein in the bryostatin-1-induced differentiation of the acute promyelocytic leukemia NB4 cell line.
Overexpression of mutant p53 has been reported to promote tumorigenicity in several cancers. However, despite its potential importance, the signals regulating mutant p53 protein expression are not known. Here we show that a form of p53 that is incapable of binding DNA is overexpressed in the acute promyelocytic leukemia NB4 cell line. Our results demonstrate that treatment of NB4 cells with bryostatin-1, which induces differentiation in this cell line, leads to hyperphosphorylation of this DNA binding-impaired form of p53 via mitogen-activated protein kinase. After this phosphorylation, the p53 protein is degraded by the ubiquitin/proteasome pathway. Furthermore, we show that inhibition of p53 hyperphosphorylation blocks p53 protein degradation and cell differentiation. In addition, inhibition of the ubiquitin/proteasome pathway also blocks p53 protein degradation and cell differentiation. These findings suggest a role for mitogen-activated protein kinase in the degradation of the DNA binding-impaired form of p53 protein and in the bryostatin-induced differentiation observed in this cell line. The implications of these results with respect to the functional significance of p53 phosphorylation and degradation in cell differentiation are discussed.
Song
X
X
Department of Biochemistry, University of California, Riverside, California 92521, USA.
Sheppard
H M
HM
Norman
A W
AW
Liu
X
X
D054713:Bryostatins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D018942:Macrolides; D008934:Mitogens / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins / Q000378:metabolism
D054713:Bryostatins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007783:Lactones; D018942:Macrolides; D008934:Mitogens; D009097:Multienzyme Complexes; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C046785:bryostatin 1; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one