Ribosomal Protein Mutations Result in Constitutive p53 Protein Degradation through Impairment of the AKT Pathway

English version České info

The p53 tumor suppressor is the most commonly mutated gene in human cancers. However, cancer cells exploit multiple mechanisms to silence the p53 pathway in addition to inactivation of the p53 gene. We previously reported that one of these mechanisms is found in tumor cells with ribosomal protein (RP) gene mutations. These cells transcribe wild type p53 mRNA yet do not stabilize p53 protein when exposed to DNA damaging agents. In this work we demonstrate that this loss of p53 protein is due to its constitutive degradation. This degradation is due to impairment of the AKT pathway, which normal signals for p53 to stabilize when the DNA is damaged. By re-activating the AKT pathway in RP-mutant cells we are able to restore p53 stabilization and activity, which may hold clinical significance for cancer treatment.

Vyšlo v časopise: Ribosomal Protein Mutations Result in Constitutive p53 Protein Degradation through Impairment of the AKT Pathway. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005326
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005326

Souhrn

Zdroje

1. Lane DP (2005) Exploiting the p53 pathway for the diagnosis and therapy of human cancer. Cold Spring Harb Symp Quant Biol 70: 489–497. 16869788

2. Horn HF, Vousden KH (2007) Coping with stress: multiple ways to activate p53. Oncogene 26: 1306–1316. 17322916

3. Carrillo J, Gonzalez A, Manguan-Garcia C, Pintado-Berninches L, Perona R (2014) p53 pathway activation by telomere attrition in X-DC primary fibroblasts occurs in the absence of ribosome biogenesis failure and as a consequence of DNA damage. Clin Transl Oncol 16: 529–538. doi: 10.1007/s12094-013-1112-3 24065372

4. Ceccaldi R, Parmar K, Mouly E, Delord M, Kim JM, et al. (2012) Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell 11: 36–49. doi: 10.1016/j.stem.2012.05.013 22683204

5. Essers PB, Pereboom TC, Goos YJ, Paridaen JT, Macinnes AW (2014) A comparative study of nucleostemin family members in zebrafish reveals specific roles in ribosome biogenesis. Dev Biol 385: 304–315. doi: 10.1016/j.ydbio.2013.10.029 24211311

6. Pereboom TC, van Weele LJ, Bondt A, MacInnes AW (2011) A zebrafish model of dyskeratosis congenita reveals hematopoietic stem cell formation failure resulting from ribosomal protein-mediated p53 stabilization. Blood 118: 5458–5465. doi: 10.1182/blood-2011-04-351460 21921046

7. Azuma M, Toyama R, Laver E, Dawid IB (2006) Perturbation of rRNA synthesis in the bap28 mutation leads to apoptosis mediated by p53 in the zebrafish central nervous system. J Biol Chem 281: 13309–13316. 16531401

8. Dutt S, Narla A, Lin K, Mullally A, Abayasekara N, et al. (2011) Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood 117: 2567–2576. doi: 10.1182/blood-2010-07-295238 21068437

9. Moniz H, Gastou M, Leblanc T, Hurtaud C, Cretien A, et al. (2012) Primary hematopoietic cells from DBA patients with mutations in RPL11 and RPS19 genes exhibit distinct erythroid phenotype in vitro. Cell Death Dis 3: e356. doi: 10.1038/cddis.2012.88 22833095

10. Vlachos A, Rosenberg PS, Atsidaftos E, Alter BP, Lipton JM (2012) Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood 119: 3815–3819. doi: 10.1182/blood-2011-08-375972 22362038

11. Boultwood J, Lewis S, Wainscoat JS (1994) The 5q-syndrome. Blood 84: 3253–3260. 7949083

12. De Keersmaecker K, Atak ZK, Li N, Vicente C, Patchett S, et al. (2013) Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nature genetics 45: 186–190. doi: 10.1038/ng.2508 23263491

13. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, et al. (2014) Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505: 495–501. doi: 10.1038/nature12912 24390350

14. Novetsky AP, Zighelboim I, Thompson DM Jr., Powell MA, Mutch DG, et al. (2013) Frequent mutations in the RPL22 gene and its clinical and functional implications. Gynecol Oncol 128: 470–474. doi: 10.1016/j.ygyno.2012.10.026 23127973

15. Chakraborty A, Uechi T, Higa S, Torihara H, Kenmochi N (2009) Loss of ribosomal protein L11 affects zebrafish embryonic development through a p53-dependent apoptotic response. PLoS One 4: e4152. doi: 10.1371/journal.pone.0004152 19129914

16. Heijnen HF, van Wijk R, Pereboom TC, Goos YJ, Seinen CW, et al. (2014) Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway. PLoS Genet 10: e1004371. doi: 10.1371/journal.pgen.1004371 24875531

17. Lai K, Amsterdam A, Farrington S, Bronson RT, Hopkins N, et al. (2009) Many ribosomal protein mutations are associated with growth impairment and tumor predisposition in zebrafish. Dev Dyn 238: 76–85. doi: 10.1002/dvdy.21815 19097187

18. Amsterdam A, Sadler KC, Lai K, Farrington S, Bronson RT, et al. (2004) Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biol 2: E139. 15138505

19. Berghmans S, Murphey RD, Wienholds E, Neuberg D, Kutok JL, et al. (2005) tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors. Proc Natl Acad Sci U S A 102: 407–412. 15630097

20. MacInnes AW, Amsterdam A, Whittaker CA, Hopkins N, Lees JA (2008) Loss of p53 synthesis in zebrafish tumors with ribosomal protein gene mutations. Proceedings of the National Academy of Sciences of the United States of America 105: 10408–10413. doi: 10.1073/pnas.0805036105 18641120

21. Choong ML, Yang H, Lee MA, Lane DP (2009) Specific activation of the p53 pathway by low dose actinomycin D: a new route to p53 based cyclotherapy. Cell Cycle 8: 2810–2818. 19657224

22. Chen CS, Ho DR, Chen FY, Chen CR, Ke YD, et al. (2014) AKT mediates actinomycin D-induced p53 expression. Oncotarget 5: 693–703. 24525337

23. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, et al. (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. The EMBO journal 15: 6541–6551. 8978681

24. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378: 785–789. 8524413

25. Kulikov R, Boehme KA, Blattner C (2005) Glycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance. Molecular and cellular biology 25: 7170–7180. 16055726

26. Kwon O, Kim KA, He L, Kim SO, Kim MS, et al. (2008) Ionizing radiation can induce GSK-3beta phosphorylation and NF-kappaB transcriptional transactivation in ATM-deficient fibroblasts. Cell Signal 20: 602–612. doi: 10.1016/j.cellsig.2007.10.022 18243662

27. Boehme KA, Kulikov R, Blattner C (2008) p53 stabilization in response to DNA damage requires Akt/PKB and DNA-PK. Proceedings of the National Academy of Sciences of the United States of America 105: 7785–7790.

28. Golling G, Amsterdam A, Sun Z, Antonelli M, Maldonado E, et al. (2002) Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development. Nature genetics 31: 135–140. 12006978

29. Boria I, Garelli E, Gazda HT, Aspesi A, Quarello P, et al. (2010) The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update. Human mutation 31: 1269–1279. doi: 10.1002/humu.21383 20960466

30. Zhang Y, Ear J, Yang Z, Morimoto K, Zhang B, et al. (2014) Defects of protein production in erythroid cells revealed in a zebrafish Diamond-Blackfan anemia model for mutation in RPS19. Cell Death Dis 5: e1352. doi: 10.1038/cddis.2014.318 25058426

31. Juarez MA, Su F, Chun S, Kiel MJ, Lyons SE (2005) Distinct roles for SCL in erythroid specification and maturation in zebrafish. J Biol Chem 280: 41636–41644. 16210319

32. Davidson AJ, Zon LI (2004) The 'definitive' (and 'primitive') guide to zebrafish hematopoiesis. Oncogene 23: 7233–7246. 15378083

33. Mikkola HK, Klintman J, Yang H, Hock H, Schlaeger TM, et al. (2003) Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature 421: 547–551. 12540851

34. Tsiftsoglou AS, Vizirianakis IS, Strouboulis J (2009) Erythropoiesis: model systems, molecular regulators, and developmental programs. IUBMB Life 61: 800–830. doi: 10.1002/iub.226 19621348

35. Danilova N, Sakamoto KM, Lin S (2011) Ribosomal protein L11 mutation in zebrafish leads to haematopoietic and metabolic defects. British journal of haematology 152: 217–228. doi: 10.1111/j.1365-2141.2010.08396.x 21114664

36. Tucker B, Lardelli M (2007) A rapid apoptosis assay measuring relative acridine orange fluorescence in zebrafish embryos. Zebrafish 4: 113–116. 18041929

37. MacInnes AW, Amsterdam A, Whittaker CA, Hopkins N, Lees JA (2008) Loss of p53 synthesis in zebrafish tumors with ribosomal protein gene mutations. Proc Natl Acad Sci U S A 105: 10408–10413. doi: 10.1073/pnas.0805036105 18641120

38. Taylor AM, Humphries JM, White RM, Murphey RD, Burns CE, et al. (2012) Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation. Exp Hematol 40: 228–237 e225. doi: 10.1016/j.exphem.2011.11.007 22120640

39. Danilova N, Sakamoto KM, Lin S (2008) Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family. Blood 112: 5228–5237. doi: 10.1182/blood-2008-01-132290 18515656

40. Duan J, Ba Q, Wang Z, Hao M, Li X, et al. (2011) Knockdown of ribosomal protein S7 causes developmental abnormalities via p53 dependent and independent pathways in zebrafish. The international journal of biochemistry & cell biology 43: 1218–1227.

41. Chen J, Ng SM, Chang C, Zhang Z, Bourdon JC, et al. (2009) p53 isoform delta113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish. Genes Dev 23: 278–290. doi: 10.1101/gad.1761609 19204115

42. Flygare J, Aspesi A, Bailey JC, Miyake K, Caffrey JM, et al. (2007) Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Blood 109: 980–986. 16990592

43. Cummings BS, Kinsey GR, Bolchoz LJ, Schnellmann RG (2004) Identification of caspase-independent apoptosis in epithelial and cancer cells. J Pharmacol Exp Ther 310: 126–134. 15028782

44. McNamee LM, Brodsky MH (2009) p53-independent apoptosis limits DNA damage-induced aneuploidy. Genetics 182: 423–435. doi: 10.1534/genetics.109.102327 19364807

45. Jia Q, Zhang Q, Zhang Z, Wang Y, Zhang W, et al. (2013) Correction: Transcriptome Analysis of the Zebrafish Model of Diamond-Blackfan Anemia from RPS19 Deficiency via p53-Dependent and-Independent Pathways. PLoS One 8.

46. Torihara H, Uechi T, Chakraborty A, Shinya M, Sakai N, et al. (2011) Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia. Br J Haematol 152: 648–654. doi: 10.1111/j.1365-2141.2010.08535.x 21223253

47. Yadav GV, Chakraborty A, Uechi T, Kenmochi N (2014) Ribosomal protein deficiency causes Tp53-independent erythropoiesis failure in zebrafish. Int J Biochem Cell Biol 49: 1–7. doi: 10.1016/j.biocel.2014.01.006 24417973

48. Payne EM, Virgilio M, Narla A, Sun H, Levine M, et al. (2012) L-Leucine improves the anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q) MDS by activating the mTOR pathway. Blood 120: 2214–2224. doi: 10.1182/blood-2011-10-382986 22734070

49. Sulima SO, Patchett S, Advani VM, De Keersmaecker K, Johnson AW, et al. (2014) Bypass of the pre-60S ribosomal quality control as a pathway to oncogenesis. Proc Natl Acad Sci U S A 111: 5640–5645. doi: 10.1073/pnas.1400247111 24706786

50. Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, et al. (2008) Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. British journal of haematology 142: 859–876. doi: 10.1111/j.1365-2141.2008.07269.x 18671700

51. Fenaux P, Preudhomme C, Quiquandon I, Jonveaux P, Lai JL, et al. (1992) Mutations of the P53 gene in acute myeloid leukaemia. British journal of haematology 80: 178–183. 1550773

52. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408: 307–310. 11099028

53. Banerji V, Frumm SM, Ross KN, Li LS, Schinzel AC, et al. (2012) The intersection of genetic and chemical genomic screens identifies GSK-3alpha as a target in human acute myeloid leukemia. J Clin Invest 122: 935–947. doi: 10.1172/JCI46465 22326953

54. Bjorklund CC, Ma W, Wang ZQ, Davis RE, Kuhn DJ, et al. (2011) Evidence of a role for activation of Wnt/beta-catenin signaling in the resistance of plasma cells to lenalidomide. The Journal of biological chemistry 286: 11009–11020. doi: 10.1074/jbc.M110.180208 21189262

55. List AF, Bennett JM, Sekeres MA, Skikne B, Fu T, et al. (2014) Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. Leukemia 28: 1033–1040. doi: 10.1038/leu.2013.305 24150217

56. Westerfield M (2000) The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio). Eugene, OR: Univ. of Oregon Press.

57. Burns CE, Traver D, Mayhall E, Shepard JL, Zon LI (2005) Hematopoietic stem cell fate is established by the Notch-Runx pathway. Genes Dev 19: 2331–2342. 16166372

58. van Rooijen E, Voest EE, Logister I, Korving J, Schwerte T, et al. (2009) Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. Blood 113: 6449–6460. doi: 10.1182/blood-2008-07-167890 19304954

59. Langheinrich U, Hennen E, Stott G, Vacun G (2002) Zebrafish as a model organism for the identification and characterization of drugs and genes affecting p53 signaling. Curr Biol 12: 2023–2028. 12477391