Identification of Alternative Splicing Variants of PPM1 Protein Phosphatase PPM1D

摘要

PPM1D, a member of the PPM1 type phosphatases which contains 605 amino acids, was originally identified as a p53-inducible protein phosphatase in response to DNA damage by ultraviolet (UV) and infrared (IR) stimulation. The phosphatase was described as a negative regulator of p53 pathway through its ability to attenuate p38 MAPK signaling [1, 2]. Recently, many other tumor suppressor proteins, such as Chk1, Chk2, ATM, and p53 itself have been identified as targets of PPM1D that are inactivated by the resulting dephosphorylation [3, 4]. The gene amplification of PPM1D has also been observed in several human cancers including breast cancer, neuroblastoma, medulloblastoma, ovarian clear cell adenocarcinoma, and pancreatic adenocarcinoma. PPM1D-deficiant mice and cells derived from them show a tumor-resistant phenotype, further suggesting that PPM1D plays a role as an oncogenic protein. On the other hand, Fiscella and coworker reported that PPM1D overexpression leads to growth suppression in a human glioblastoma cell line, suggesting that PPM1D might contribute to growth inhibitory pathways [5]. The mechanism on the different effects by PPM1D overexpression has remained obscure. In this study, we identified an alternative splicing variant of PPM1D (PPM1Das) in addition to the originally reported PPM1D protein in breast cancer MCF7 cells and characterized these two enzymes at the mRNA and protein levels.