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Phosphatidylinositol-3 kinase-dependent translational regulation of Id1 involves the PPM1G phosphatase

Oncogene volume 35, pages 5807–5816 (2016)Cite this article

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Abstract

Id1 is a helix-loop-helix transcriptional modulator that increases the aggressiveness of malignant glial neoplasms. Since most glioblastomas (GBMs) show increased phosphatidylinositol-3 kinase (PI-3K) signaling, we sought to determine whether this pathway regulates Id1 expression. Higher basal Id1 expression correlates with dysregulated PI-3K signaling in multiple established GBM cell lines. Further characterization of PI-3K-dependent Id1 regulation reveals that chemical or genetic inhibition of PI-3K signaling reduces Id1 protein but not mRNA expression. Overall, PI-3K signaling appears to enhance Id1 translation with no significant effect on its stability. PI-3K signaling is known to regulate protein translation through mTORC1-dependent phosphorylation of 4E-BP1, which reduces its association with and inhibition of the translation initiation factor eIF4E. Interestingly, while inhibition of PI-3K and AKT lowers 4E-BP1 phosphorylation and expression of Id1 in all cases, inhibition of TORC1 with rapamycin does not consistently have a similar effect, suggesting an alternative mechanism for PI-3K-dependent regulation of Id1 translation. We now identify a potential role for the serine–threonine phosphatase PPM1G in translational regulation of Id1 protein expression. PPM1G knockdown by siRNA increase both 4E-BP1 phosphorylation and Id1 expression and PPM1G and 4E-BP1 co-associates in GBM cells. Furthermore, PPM1G is a phosphoprotein and this phosphorylation appears to be regulated by PI-3K activity. Finally, PI-3K inhibition increases PPM1G activity when assessed by an in vitro phosphatase assay. Our findings provide the first evidence that the PI-3K/AKT signaling pathway modulates PPM1G activity resulting in a shift in the balance between hyper- and hypo-phosphorylated 4E-BP1 and translational regulation of Id1 expression.

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References

  1. Van Meir E, Hadjipanayis C, Norden A, Shu H, Wen P, Olson J . Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 2010; 60: 166–193.

    Article  Google Scholar 

  2. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061–1068.

    Article  Google Scholar 

  3. Norton J, Deed R, Craggs G, Sablitzky F . Id helix-loop-helix proteins in cell growth and differentiation. Trends Cell Biol 1998; 8: 58–65.

    CAS  PubMed  Google Scholar 

  4. Ruzinova M, Benezra R . Id proteins in development, cell cycle and cancer. Trends Cell Biol 2003; 13: 410–418.

    Article  CAS  Google Scholar 

  5. Lasorella A, Benezra R, Iavarone A . The ID proteins: master regulators of cancer stem cells and tumour aggressiveness. Nat Rev Cancer 2014; 14: 77–91.

    Article  CAS  Google Scholar 

  6. Lasorella A, Uo T, Iavarone A . Id proteins at the cross-road of development and cancer. Oncogene 2001; 20: 8326–8333.

    Article  CAS  Google Scholar 

  7. Schindl M, Oberhuber G, Obermair A, Schoppmann S, Karner B, Birner P . Overexpression of Id-1 protein is a marker for unfavorable prognosis in early-stage cervical cancer. Cancer Res 2001; 61: 5703–5706.

    CAS  PubMed  Google Scholar 

  8. Schindl M, Schoppmann S, Strobel T, Heinzl H, Leisser C, Horvat R et al. Level of Id-1 protein expression correlates with poor differentiation, enhanced malignant potential, and more aggressive clinical behavior of epithelial ovarian tumors. Clin Cancer Res 2003; 9: 779–785.

    CAS  Google Scholar 

  9. Vandeputte D, Troost D, Leenstra S, Ijlst-Keizers H, Ramkema M, Bosch D et al. Expression and distribution of id helix-loop-helix proteins in human astrocytic tumors. Glia 2002; 38: 329–338.

    Article  Google Scholar 

  10. Anido J, Saez-Borderias A, Gonzalez-Junca A, Rodon L, Folch G, Carmona M et al. TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell 2010; 18: 655–668.

    Article  CAS  Google Scholar 

  11. Barrett L, Granot Z, Coker C, Iavarone A, Hambardzumyan D, Holland E et al. Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma. Cancer Cell 2012; 21: 11–24.

    Article  CAS  Google Scholar 

  12. Niola F, Zhao X, Singh D, Sullivan R, Castano A, Verrico A et al. Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis. J Clin Invest 2013; 123: 405–417.

    Article  CAS  Google Scholar 

  13. Xu K, Wang L, Shu H . COX-2 overexpression increases malignant potential of human glioma cells through Id1. Oncotarget 2014; 5: 1241–1252.

    PubMed  Google Scholar 

  14. Murray M, Kobayashi R, Krainer A . The type 2C Ser/Thr phosphatase PP2Cgamma is a pre-mRNA splicing factor. Genes Dev 1999; 13: 87–97.

    Article  CAS  Google Scholar 

  15. Kimura H, Takizawa N, Allemand E, Hori T, Iborra F, Nozaki N et al. A novel histone exchange factor, protein phosphatase 2Cgamma, mediates the exchange and dephosphorylation of H2A-H2B. J Cell Biol 2006; 175: 389–400.

    Article  CAS  Google Scholar 

  16. Allemand E, Hastings M, Murray M, Myers M, Krainer A . Alternative splicing regulation by interaction of phosphatase PP2Cgamma with nucleic acid-binding protein YB-1. Nat Struct Mol Biol 2007; 14: 630–638.

    Article  CAS  Google Scholar 

  17. Beli P, Lukashchuk N, Wagner S, Weinert B, Olsen J, Baskcomb L et al. Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response. Mol Cell 2012; 46: 212–225.

    Article  CAS  Google Scholar 

  18. Khoronenkova S, Dianova I, Ternette N, Kessler B, Parsons J, Dianov G . ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage. Mol Cell 2012; 45: 801–813.

    Article  CAS  Google Scholar 

  19. Bounpheng M, Dimas J, Dodds S, Christy B . Degradation of Id proteins by the ubiquitin-proteasome pathway. FASEB J 1999; 13: 2257–2264.

    Article  CAS  Google Scholar 

  20. Anand G, Yin X, Shahidi A, Grove L, Prochownik E . Novel regulation of the helix-loop-helix protein Id1 by S5a, a subunit of the 26 S proteasome. J Biol Chem 1997; 272: 19140–19151.

    Article  CAS  Google Scholar 

  21. Roux P, Topisirovic I . Regulation of mRNA translation by signaling pathways. Cold Spring Harb Perspect Biol 2012; 4: pii: a012252.

    Article  Google Scholar 

  22. Thoreen C, Chantranupong L, Keys H, Wang T, Gray N, Sabatini D . A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 2012; 485: 109–113.

    Article  CAS  Google Scholar 

  23. Liu J, Stevens P, Eshleman N, Gao T . Protein phosphatase PPM1G regulates protein translation and cell growth by dephosphorylating 4E binding protein 1 (4E-BP1). J Biol Chem 2013; 288: 23225–23233.

    Article  CAS  Google Scholar 

  24. Brennan C, Verhaak R, McKenna A, Campos B, Noushmehr H, Salama S et al. The somatic genomic landscape of glioblastoma. Cell 2013; 155: 462–477.

    Article  CAS  Google Scholar 

  25. Thoreen C, Kang S, Chang J, Liu Q, Zhang J, Gao Y et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009; 284: 8023–8032.

    Article  CAS  Google Scholar 

  26. Travis S, Welsh M . PP2C gamma: a human protein phosphatase with a unique acidic domain. FEBS Lett 1997; 412: 415–419.

    Article  CAS  Google Scholar 

  27. Petri S, Grimmler M, Over S, Fischer U, Gruss O . Dephosphorylation of survival motor neurons (SMN) by PPM1G/PP2Cgamma governs Cajal body localization and stability of the SMN complex. J Cell Biol 2007; 179: 451–465.

    Article  CAS  Google Scholar 

  28. Foster W, Langenbacher A, Gao C, Chen J, Wang Y . Nuclear phosphatase PPM1G in cellular survival and neural development. Dev Dyn 2013; 242: 1101–1109.

    Article  CAS  Google Scholar 

  29. Matsuoka S, Ballif B, Smogorzewska A, McDonald E 3rd, Hurov K, Luo J et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 2007; 316: 1160–1166.

    Article  CAS  Google Scholar 

  30. Dephoure N, Zhou C, Villen J, Beausoleil S, Bakalarski C, Elledge S et al. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci USA 2008; 105: 10762–10767.

    Article  CAS  Google Scholar 

  31. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474: 609–615.

    Article  Google Scholar 

  32. Cancer Genome Atlas Research Network Kandoth C, Schultz N, Cherniack A, Akbani R, Liu Y, Shen H et alCancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497: 67–73.

    Article  Google Scholar 

  33. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–337.

    Article  Google Scholar 

  34. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61–70.

    Article  Google Scholar 

  35. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489: 519–525.

    Article  Google Scholar 

  36. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

    Article  Google Scholar 

  37. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013; 499: 43–49.

    Article  Google Scholar 

  38. Cancer Genome Atlas Research Network Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K et alCancer Genome Atlas Research Network. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet 2013; 45: 1113–1120.

    Article  Google Scholar 

  39. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507: 315–322.

    Article  Google Scholar 

  40. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014; 511: 543–550.

    Article  Google Scholar 

  41. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014; 513: 202–209.

    Article  Google Scholar 

  42. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015; 517: 576–582.

    Article  Google Scholar 

  43. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014; 159: 676–690.

    Article  Google Scholar 

  44. Cancer Genome Atlas Research Network Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA et alCancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015; 372: 2481–2498.

    Article  Google Scholar 

  45. Verhaak R, Hoadley K, Purdom E, Wang V, Qi Y, Wilkerson M et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010; 17: 98–110.

    Article  CAS  Google Scholar 

  46. Rajasekhar V, Viale A, Socci N, Wiedmann M, Hu X, Holland E . Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell 2003; 12: 889–901.

    Article  CAS  Google Scholar 

  47. Helmy K, Halliday J, Fomchenko E, Setty M, Pitter K, Hafemeister C et al. Identification of global alteration of translational regulation in glioma in vivo. PLoS One 2012; 7: e46965.

    Article  CAS  Google Scholar 

  48. Xu K, Shu H . EGFR activation results in enhanced cyclooxygenase-2 expression through p38 mitogen-activated protein kinase-dependent activation of the Sp1/Sp3 transcription factors in human gliomas. Cancer Res 2007; 67: 6121–6129.

    Article  CAS  Google Scholar 

  49. Lu R, Wang H, Liang Z, Ku L, O'Donnell W, Li W et al. The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development. Proc Natl Acad Sci USA 2004; 101: 15201–15206.

    Article  CAS  Google Scholar 

  50. Perry D, Kitatani K, Roddy P, El-Osta M, Hannun Y . Identification and characterization of protein phosphatase 2C activation by ceramide. J Lipid Res 2012; 53: 1513–1521.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Walter Curran for providing departmental funding support and Dr Chi-Ming Chang for helpful discussion in regard to this project. This work was supported in part by a grant (to H-KGS) from the Southeast Brain Tumor Foundation and a Cancer Center grant from the National Cancer Institute (P30-CA138292).

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Authors and Affiliations

  1. Department of Radiation Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA, USA

    K Xu, L Wang & H-KG Shu

  2. Department of Pharmacology, Emory University, Atlanta, GA, USA

    W Feng & Y Feng

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Correspondence to H-KG Shu.

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Xu, K., Wang, L., Feng, W. et al. Phosphatidylinositol-3 kinase-dependent translational regulation of Id1 involves the PPM1G phosphatase. Oncogene 35, 5807–5816 (2016). https://doi.org/10.1038/onc.2016.115

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