Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity.
Expression of oncogenic Ras in primary human cells activates p53, thereby protecting cells from transformation. We show that in Ras-expressing IMR-90 cells, p53 is phosphorylated at Ser33 and Ser46 by the p38 mitogen-activated protein kinase (MAPK). Activity of p38 MAPK is regulated by the p53-inducible phosphatase PPM1D, creating a potential feedback loop. Expression of oncogenic Ras suppresses PPM1D mRNA induction, leaving p53 phosphorylated at Ser33 and Ser46 and in an active state. Retrovirus-mediated overexpression of PPM1D reduced p53 phosphorylation at these sites, abrogated Ras-induced apoptosis and partially rescued cells from cell-cycle arrest. Inactivation of p38 MAPK (the product of Mapk14) in vivo by gene targeting or by PPM1D overexpression expedited tumor formation after injection of mouse embryo fibroblasts (MEFs) expressing E1A+Ras into nude mice. The gene encoding PPM1D (PPM1D, at 17q22/q23) is amplified in human breast-tumor cell lines and in approximately 11% of primary breast tumors, most of which harbor wildtype p53. These findings suggest that inactivation of the p38 MAPK through PPM1D overexpression resulting from PPM1D amplification contributes to the development of human cancers by suppressing p53 activation.
Bulavin
Dmitry V
DV
Gene Response Section, Bethesda, Maryland 20892, USA.
Demidov
Oleg N
ON
Saito
Shin'ichi
S
Kauraniemi
Paivikki
P
Phillips
Crissy
C
Amundson
Sally A
SA
Ambrosino
Concetta
C
Sauter
Guido
G
Nebreda
Angel R
AR
Anderson
Carl W
CW
Kallioniemi
Anne
A
Fornace
Albert J
AJ
Appella
Ettore
E
D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000502:physiology; D009363:Neoplasm Proteins; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C