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Gene Review

PPM1D  -  protein phosphatase, Mg2+/Mn2+ dependent, 1D

Homo sapiens

Synonyms: PP2C-DELTA, PP2C-delta, Protein phosphatase 1D, Protein phosphatase 2C isoform delta, Protein phosphatase magnesium-dependent 1 delta, ...
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Disease relevance of PPM1D


High impact information on PPM1D


Chemical compound and disease context of PPM1D


Biological context of PPM1D

  • PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation [7].
  • PPM1D is an oncogene in transformation assays and is amplified or overexpressed in several human tumor types [10].
  • Thus, PPM1D may inhibit BER by dephosphorylating UNG2 to facilitate its inactivation after completion of DNA repair [10].
  • Point mutations that inactivate PPM1D phosphatase activity abrogate BER suppression, indicating that dephosphorylation by PPM1D is important for BER inhibition [10].
  • Moreover, down-regulation of PPM1D by transfection of an antisense oligonucleotide suppressed the growth of NB cell lines to a remarkable degree, at least partly by participating in a process leading to apoptotic cell death [1].

Anatomical context of PPM1D

  • In turn, deletion of the inhibitory ATM phosphatase, Wip1, results in ATM up-regulation and suppression of Emu-myc-induced B cell lymphomas [11].
  • Reduced expression of Wip1 and BRCA-2 region transcription unit CG005 was significantly correlated with poorer differentiation of HCCs, and mRNA expression of these genes was significantly reduced in HCCs associated with portal vein involvement compared with HCCs without such involvement [12].

Associations of PPM1D with chemical compounds


Physical interactions of PPM1D


Enzymatic interactions of PPM1D


Regulatory relationships of PPM1D


Other interactions of PPM1D

  • Here, we demonstrate that PPM1D interacts with the nuclear isoform of uracil DNA glycosylase, UNG2, and suppresses base excision repair (BER) [10].
  • In this review we summarize the structural studies of the amplicon that have been carried out, we outline the evidence implicating the RPS6KB1, TBX2, and PPM1D genes as oncogenes, and we describe some of the other candidate oncogenes from the region [15].
  • Overexpression of Wip1 was inversely correlated with that of active (phosphor-) p38 MAPK (P = 0.007) [5].
  • Interestingly, PPM1D amplification was associated with ERBB2 expression (p=0.0001) thus implying that PPM1D aberrations occurs in tumours with poor prognosis [16].
  • In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage [17].

Analytical, diagnostic and therapeutic context of PPM1D

  • Among 15 candidate genes within the 17q21-q24 region, we found significantly elevated expression of PPM1D and APPBP2, and their heightened expression correlated negatively with disease-free survival (P = 0.0090, log-rank test adjusted for multiple comparisons) [18].
  • PPM1D copy number analysis showed amplification in 11% (13/117) of the tumours and quantitative real-time RT-PCR revealed a significant correlation (p=0.0148) between PPM1D amplification and increased expression [16].
  • Three-dimension homology models of Wip1 with bound substrate peptides were constructed, and site-directed mutagenesis was performed to confirm the importance of specific residues for substrate recognition [19].


  1. PPM1D is a potential target for 17q gain in neuroblastoma. Saito-Ohara, F., Imoto, I., Inoue, J., Hosoi, H., Nakagawara, A., Sugimoto, T., Inazawa, J. Cancer Res. (2003) [Pubmed]
  2. Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. Mendrzyk, F., Radlwimmer, B., Joos, S., Kokocinski, F., Benner, A., Stange, D.E., Neben, K., Fiegler, H., Carter, N.P., Reifenberger, G., Korshunov, A., Lichter, P. J. Clin. Oncol. (2005) [Pubmed]
  3. Augmented cancer resistance and DNA damage response phenotypes in PPM1D null mice. Nannenga, B., Lu, X., Dumble, M., Van Maanen, M., Nguyen, T.A., Sutton, R., Kumar, T.R., Donehower, L.A. Mol. Carcinog. (2006) [Pubmed]
  4. Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Li, J., Yang, Y., Peng, Y., Austin, R.J., van Eyndhoven, W.G., Nguyen, K.C., Gabriele, T., McCurrach, M.E., Marks, J.R., Hoey, T., Lowe, S.W., Powers, S. Nat. Genet. (2002) [Pubmed]
  5. Overexpression of the wip1 gene abrogates the p38 MAPK/p53/Wip1 pathway and silences p16 expression in human breast cancers. Yu, E., Ahn, Y.S., Jang, S.J., Kim, M.J., Yoon, H.S., Gong, G., Choi, J. Breast Cancer Res. Treat. (2007) [Pubmed]
  6. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Bulavin, D.V., Demidov, O.N., Saito, S., Kauraniemi, P., Phillips, C., Amundson, S.A., Ambrosino, C., Sauter, G., Nebreda, A.R., Anderson, C.W., Kallioniemi, A., Fornace, A.J., Appella, E. Nat. Genet. (2002) [Pubmed]
  7. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Lu, X., Nannenga, B., Donehower, L.A. Genes Dev. (2005) [Pubmed]
  8. Dual roles for the phosphatase PPM1D in regulating progesterone receptor function. Proia, D.A., Nannenga, B.W., Donehower, L.A., Weigel, N.L. J. Biol. Chem. (2006) [Pubmed]
  9. Chemical inhibition of Wip1 phosphatase contributes to suppression of tumorigenesis. Belova, G.I., Demidov, O.N., Fornace, A.J., Bulavin, D.V. Cancer Biol. Ther. (2005) [Pubmed]
  10. The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair. Lu, X., Bocangel, D., Nannenga, B., Yamaguchi, H., Appella, E., Donehower, L.A. Mol. Cell (2004) [Pubmed]
  11. Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase. Shreeram, S., Hee, W.K., Demidov, O.N., Kek, C., Yamaguchi, H., Fornace, A.J., Anderson, C.W., Appella, E., Bulavin, D.V. J. Exp. Med. (2006) [Pubmed]
  12. MRNA expression of genes altered by 5-azacytidine treatment in cancer cell lines is associated with clinicopathological parameters of human cancers. Kanai, Y., Ushijima, S., Saito, Y., Nakanishi, Y., Sakamoto, M., Hirohashi, S. J. Cancer Res. Clin. Oncol. (2001) [Pubmed]
  13. p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. Takekawa, M., Adachi, M., Nakahata, A., Nakayama, I., Itoh, F., Tsukuda, H., Taya, Y., Imai, K. EMBO J. (2000) [Pubmed]
  14. Development of a Substrate-Based Cyclic Phosphopeptide Inhibitor of Protein Phosphatase 2Cdelta, Wip1. Yamaguchi, H., Durell, S.R., Feng, H., Bai, Y., Anderson, C.W., Appella, E. Biochemistry (2006) [Pubmed]
  15. The 17q23 amplicon and breast cancer. Sinclair, C.S., Rowley, M., Naderi, A., Couch, F.J. Breast Cancer Res. Treat. (2003) [Pubmed]
  16. The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. Rauta, J., Alarmo, E.L., Kauraniemi, P., Karhu, R., Kuukasjärvi, T., Kallioniemi, A. Breast Cancer Res. Treat. (2006) [Pubmed]
  17. Wip1 phosphatase modulates ATM-dependent signaling pathways. Shreeram, S., Demidov, O.N., Hee, W.K., Yamaguchi, H., Onishi, N., Kek, C., Timofeev, O.N., Dudgeon, C., Fornace, A.J., Anderson, C.W., Minami, Y., Appella, E., Bulavin, D.V. Mol. Cell (2006) [Pubmed]
  18. Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. Hirasawa, A., Saito-Ohara, F., Inoue, J., Aoki, D., Susumu, N., Yokoyama, T., Nozawa, S., Inazawa, J., Imoto, I. Clin. Cancer Res. (2003) [Pubmed]
  19. Substrate specificity of the human protein phosphatase 2Cdelta, Wip1. Yamaguchi, H., Minopoli, G., Demidov, O.N., Chatterjee, D.K., Anderson, C.W., Durell, S.R., Appella, E. Biochemistry (2005) [Pubmed]
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