title: Protein phosphatase 1 inhibits p53 signaling by dephosphorylating and stabilizing Mdmx.
abstract: The activation and stabilization of the p53 protein play a major role in the DNA damage response. Protein levels of p53 are tightly controlled by transcriptional regulation and a number of positive and negative posttranslational modifiers, including kinases, phosphatases, E3 ubiquitin ligases, deubiquitinases, acetylases and deacetylases. One of the primary p53 regulators is Mdmx. Despite its RING domain and structural similarity with Mdm2, Mdmx does not have an intrinsic ligase activity, but inhibits the transcriptional activity of p53. Previous studies reported that Mdmx is phosphorylated and destabilized in response to DNA damage stress. Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. Our results suggest that PP1 is a crucial component in the ATM-Chk2-p53 signaling pathway.
authors.affiliation: Department of Radiology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing 312000, China.
authors.forename: Zengxin
authors.initials: Z
authors.lastname: Lu
authors.forename: Guohui
authors.initials: G
authors.lastname: Wan
authors.forename: Huarong
authors.initials: H
authors.lastname: Guo
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
mesh_terms: D019943:Amino Acid Substitution; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D054645:Protein Phosphatase 1