Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity

Abstract

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.

The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

“…We found that the onset of mammary gland tumors was reverted in triple MMTV-ErbB2/PPM1D/MKK6 transgenics compared to MMTV-ErbB2/PPM1D mice (Figure 3a). Wip1 phosphatase in breast cancer ON Demidov et al (Bulavin et al, 2002(Bulavin et al, , 2004. We previously found that activation of p38 MAPK could be critical in rendering Wip1-deficient mice resistant to mammary gland tumors driven by ErbB2 (Bulavin et al, 2004).…”

“…Further evidence with a rodent fibroblast transformation assay showed that introduction of Wip1 along with Ras, Myc, or ErbB2 resulted in enhanced colony formation in soft agar and led to the development of tumors when these cells were explanted into nude mice (Bulavin et al, 2002). These findings suggested that Wip1 phosphatase has oncogenic potential (Bulavin et al, 2002;Li et al, 2002;Hirasawa et al, 2003;Saito-Ohara et al, 2003).…”

“…Through a combination of genetic and molecular studies, it was established that Wip1 functions in a linear pathway with p53 (Bulavin et al, 2002;Li et al, 2002). A large majority of primary breast tumors that overexpress Wip1 have a structurally intact p53 gene, implying that Wip1 may contribute to the functional inactivation of p53 (Bulavin et al, 2002;Rauta et al, 2006).…”

“…A large majority of primary breast tumors that overexpress Wip1 have a structurally intact p53 gene, implying that Wip1 may contribute to the functional inactivation of p53 (Bulavin et al, 2002;Rauta et al, 2006). Further evidence with a rodent fibroblast transformation assay showed that introduction of Wip1 along with Ras, Myc, or ErbB2 resulted in enhanced colony formation in soft agar and led to the development of tumors when these cells were explanted into nude mice (Bulavin et al, 2002). These findings suggested that Wip1 phosphatase has oncogenic potential (Bulavin et al, 2002;Li et al, 2002;Hirasawa et al, 2003;Saito-Ohara et al, 2003).…”

“…This data is in agreement with previously published results showing that Wip1 is a weak oncogene. However, Wip1 can complement in vitro other oncogenes, such as Ras and ErbB2, in their ability to transform mouse embryo fibroblasts, yet with low efficiency (Bulavin et al, 2002). To understand whether Wip1 phosphatase can cooperate with other oncogenes in promoting tumorigenesis in vivo, we crossed MMTV-PPM1D mice with mice expressing an MMTV-ErbB2 transgene.…”