#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Corp Regulates P53 in via a Negative Feedback Loop


Organisms have exquisitely sensitive mechanisms to detect and respond to DNA damage. If DNA damage in a cell can be repaired, then that cell may resume its normal function. In multi-cellular organisms, if a cell cannot repair DNA damage it usually undergoes programmed cell death. This prevents the proliferation of cells with damaged genomes, which might otherwise differentiate incorrectly or proliferate without limit as cancer. In Drosophila melanogaster we identified corp as a gene that promotes the survival of such cells. Transcription of corp is activated by the P53 tumor suppressor protein, known primarily for its induction of cell death in response to DNA damage. Our experiments show that P53 regulates both pro-death and anti-death genes, and that a competition between these opposing factors determines cell fate. We find that corp functions by down-regulating P53, establishing a negative feedback loop. In vertebrates an identical mode of regulation is known: P53 up-regulates Mdm2, which physically interacts with P53 and is its primary negative regulator. We identified a protein motif on Corp that is shared with Mdm2, and is required for physical interaction between Corp and Drosophila P53. These results reinforce and strengthen the similarities of the P53 pathways and their regulation in vertebrates and in Drosophila.


Vyšlo v časopise: Corp Regulates P53 in via a Negative Feedback Loop. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005400
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005400

Souhrn

Organisms have exquisitely sensitive mechanisms to detect and respond to DNA damage. If DNA damage in a cell can be repaired, then that cell may resume its normal function. In multi-cellular organisms, if a cell cannot repair DNA damage it usually undergoes programmed cell death. This prevents the proliferation of cells with damaged genomes, which might otherwise differentiate incorrectly or proliferate without limit as cancer. In Drosophila melanogaster we identified corp as a gene that promotes the survival of such cells. Transcription of corp is activated by the P53 tumor suppressor protein, known primarily for its induction of cell death in response to DNA damage. Our experiments show that P53 regulates both pro-death and anti-death genes, and that a competition between these opposing factors determines cell fate. We find that corp functions by down-regulating P53, establishing a negative feedback loop. In vertebrates an identical mode of regulation is known: P53 up-regulates Mdm2, which physically interacts with P53 and is its primary negative regulator. We identified a protein motif on Corp that is shared with Mdm2, and is required for physical interaction between Corp and Drosophila P53. These results reinforce and strengthen the similarities of the P53 pathways and their regulation in vertebrates and in Drosophila.


Zdroje

1. Zhou B-BS, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408: 433–439. 11100718

2. Sancar AA, Lindsey-Boltz LAL, Unsal-Kaçmaz KK, Linn SS (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Biochemistry 73: 39–85.

3. Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461: 1071–1078. doi: 10.1038/nature08467 19847258

4. Ahmad K, Golic KG (1999) Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. Genetics 151: 1041–1051. 10049921

5. Titen SWA, Golic KG (2008) Telomere Loss Provokes Multiple Pathways to Apoptosis and Produces Genomic Instability in Drosophila melanogaster. Genetics 180: 1821–1832. doi: 10.1534/genetics.108.093625 18845846

6. Golic KG (1994) Local Transposition of P Elements in Drosophila Melanogaster and Recombination between Duplicated Elements Using a Site-Specific Recombinase. Genetics 137: 551. 8070665

7. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253: 49–53. 1905840

8. Hirao A (2000) DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2. Science 287: 1824–1827. 10710310

9. Matsuoka S, Huang M, Elledge SJ (1998) Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282: 1893–1897. 9836640

10. Chaturvedi PP, Eng WKW, Zhu YY, Mattern MRM, Mishra RR, et al. (1999) Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18: 4047–4054. 10435585

11. Chehab NHN, Malikzay AA, Appel MM, Halazonetis TDT (2000) Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes & Development 14: 278–288.

12. Wahl GM, Carr AM (2001) The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nat Cell Biol 3: E277–E286. 11781586

13. Liu Y (2001) p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding. Carcinogenesis 22: 851–860. 11375889

14. Akdemir F, Christich A, Sogame N, Chapo J, Abrams JM (2007) p53 directs focused genomic responses in Drosophila. Oncogene 26: 5184–5193. 17310982

15. Brodsky MH, Weinert BT, Tsang G, Rong YS, McGinnis NM, et al. (2004) Drosophila melanogaster MNK/Chk2 and p53 Regulate Multiple DNA Repair and Apoptotic Pathways following DNA Damage. Molecular and Cellular Biology 24: 1219–1231. 14729967

16. Colombani J, Polesello C, Josué F, Tapon N (2006) Dmp53 activates the Hippo pathway to promote cell death in response to DNA damage. Curr Biol 16: 1453–1458. 16860746

17. Lee JH, Lee E, Park J, Kim E, Kim J, et al. (2003) In vivo p53 function is indispensable for DNA damage-induced apoptotic signaling in Drosophila. FEBS Letters 550: 5–10. 12935877

18. Vousden KH, Lu X (2002) Live or let die: the cell's response to p53. Nat Rev Cancer 2: 594–604. 12154352

19. Donehower LAL, Harvey MM, Slagle BLB, McArthur MJM, Montgomery CAC, et al. (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215–221. 1552940

20. Kurzhals RL, Titen SWA, Xie HB, Golic KG (2011) Chk2 and p53 are haploinsufficient with dependent and independent functions to eliminate cells after telomere loss. PLoS Genet 7: e1002103–e1002103. doi: 10.1371/journal.pgen.1002103 21655087

21. Brodsky MH, Nordstrom W, Tsang G, Kwan E, Rubin GM, et al. (2000) Drosophila p53 Binds a Damage Response Element at the reaper Locus. Cell 101: 103–113. 10778860

22. Ollmann M, Young LM, Di Como CJ, Karim F, Belvin M, et al. (2000) Drosophila p53 is a structural and functional homolog of the tumor suppressor p53. Cell 101: 91–101. 10778859

23. Jin S, Martinek S, Joo WS, Wortman JR, Mirkovic N, et al. (2000) Identification and characterization of a p53 homologue in Drosophila melanogaster. Proc Natl Acad Sci USA 97: 7301–7306. 10860994

24. Kubbutat MHG, Jones S, Vousden KH (1997) Regulation of p53 stability by Mdm2. Proc Natl Acad Sci USA 387: 299–303.

25. Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69: 1237–1245. 1535557

26. Peters M, DeLuca C, Hirao A, Stambolic V, Potter J, et al. (2002) Chk2 regulates irradiation-induced, p53-mediated apoptosis in Drosophila. proc Natl Acad Sci USA 99: 11305–11310. 12172011

27. Zhang Y, Lin N, Carroll PM, Chan G, Guan B, et al. (2008) Epigenetic Blocking of an Enhancer Region Controls Irradiation-Induced Proapoptotic Gene Expression in Drosophila Embryos. Developmental Cell 14: 481–493. doi: 10.1016/j.devcel.2008.01.018 18410726

28. Rørth PP (1996) A modular misexpression screen in Drosophila detecting tissue-specific phenotypes. Proc Natl Acad Sci USA 93: 12418–12422. 8901596

29. Hauck BB, Gehring WJW, Walldorf UU (1999) Functional analysis of an eye specific enhancer of the eyeless gene in Drosophila. Proc Natl Acad Sci USA 96: 564–569. 9892673

30. Fan Y, Bergmann A (2008) Distinct Mechanisms of Apoptosis-Induced Compensatory Proliferation in Proliferating and Differentiating Tissues in the Drosophila Eye. Developmental Cell 14: 399–410. doi: 10.1016/j.devcel.2008.01.003 18331718

31. Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118: 401–415. 8223268

32. Tabata T, Schwartz C, Gustavson E, Ali Z, Kornberg TB (1995) Creating a Drosophila wing de novo, the role of engrailed, and the compartment border hypothesis. Development 121: 3359–3369. 7588069

33. Ahmad K, Golic KG (1998) The transmission of fragmented chromosomes in Drosophila melanogaster. Genetics 148: 775–792. 9504924

34. Titen SWA, Golic KG (2010) Healing of euchromatic chromosome breaks by efficient de novo telomere addition in Drosophila melanogaster. Genetics 184: 309–312. doi: 10.1534/genetics.109.109934 19897748

35. Titen SWA, Lin H-C, Bhandari J, Golic KG (2014) Chk2 and p53 regulate the transmission of healed chromosomes in the Drosophila male germline. PLoS Genet 10: e1004130–e1004130. doi: 10.1371/journal.pgen.1004130 24586185

36. Shlevkov E, Morata G (2012) A dp53/JNK-dependant feedback amplification loop is essential for the apoptotic response to stress in Drosophila. Cell Death Differ 19: 451–460. doi: 10.1038/cdd.2011.113 21886179

37. Bailey TLT, Elkan CC (1994) Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proc Int Conf Intell Syst Mol Biol 2: 28–36. 7584402

38. Bailey TLT, Williams NN, Misleh CC, Li WWW (2006) MEME: discovering and analyzing DNA and protein sequence motifs. Nucleic Acids Research 34: W369–W373. 16845028

39. Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, et al. (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274: 948–953. 8875929

40. Poyurovsky MV, Katz C, Laptenko O, Beckerman R, Lokshin M, et al. (2010) The C terminus of p53 binds the N-terminal domain of MDM2. Nature Structural & Molecular Biology 17: 982–989.

41. Kulikov R, Winter M, Blattner C (2006) Binding of p53 to the central domain of Mdm2 is regulated by phosphorylation. J Biol Chem 281: 28575–28583. doi: 10.1074/jbc.M513311200 16870621

42. Sogame N, Kim M, Abrams JM (2003) Drosophila p53 preserves genomic stability by regulating cell death. Proc Natl Acad Sci USA 100: 4696–4701. 12672954

43. Nordstrom W, Abrams JM (2000) Guardian ancestry: fly p53 and damage-inducible apoptosis. Cell Death Differ 7: 1035–1038. 11139275

44. Manfredi JJ (2010) The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes & Development 24: 1580–1589.

45. Jones SN, Roe AE, Donehower LA, Bradley A (1995) Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378: 206–208. 7477327

46. Pant V, Xiong S, Jackson JG, Post SM, Abbas HA, et al. (2013) The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity. Genes & Development 27: 1857–1867.

47. Tollini LA, Jin A, Park J, Zhang Y (2014) Regulation of p53 by Mdm2 E3 Ligase Function Is Dispensable in Embryogenesis and Development, but Essential in Response to DNA Damage. Cancer Cell 26: 235–247. doi: 10.1016/j.ccr.2014.06.006 25117711

48. Guruharsha KG, Rual J-F, Zhai B, Mintseris J, Vaidya P, et al. (2011) A protein complex network of Drosophila melanogaster. Cell 147: 690–703. doi: 10.1016/j.cell.2011.08.047 22036573

49. Callaghan MJ, Russell AJ, Woollatt E, Sutherland GR, Sutherland RL, et al. (1998) Identification of a human HECT family protein with homology to the Drosophila tumor suppressor gene hyperplastic discs. Oncogene 17: 3479–3491. 10030672

50. Allton K, Jain AK, Herz H-M, Tsai W-W, Jung SY, et al. (2009) Trim24 targets endogenous p53 for degradation. Proc Natl Acad Sci USA 106: 11612–11616. doi: 10.1073/pnas.0813177106 19556538

51. Chen S, Wei H-M, Lv W-W, Wang D-L, Sun F-L (2011) E2 ligase dRad6 regulates DMP53 turnover in Drosophila. Journal of Biological Chemistry 286: 9020–9030. doi: 10.1074/jbc.M110.190314 21205821

52. Zhang W, Durocher D (2010) De novo telomere formation is suppressed by the Mec1-dependent inhibition of Cdc13 accumulation at DNA breaks. Genes & Development 24: 502–515.

53. Oikemus SR (2004) Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect. Genes & Development 18: 1850–1861.

54. Bilak A, Uyetake L, Su TT (2014) Dying cells protect survivors from radiation-induced cell death in Drosophila. PLoS Genet 10: e1004220. doi: 10.1371/journal.pgen.1004220 24675716

55. Xie HB, Golic KG (2004) Gene Deletions by Ends-In Targeting in Drosophila melanogaster. Genetics 168: 1477–1489. doi: 10.1534/genetics.104.030882 15579700

56. Rørth P (1998) Gal4 in the Drosophila female germline. Mechanisms of Development 78: 113–118. 9858703

57. Freeman M (1996) Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87: 651–660. 8929534

58. Bischof JJ, Maeda RKR, Hediger MM, Karch FF, Basler KK (2007) An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases. Proc Natl Acad Sci USA 104: 3312–3317. 17360644

59. Moon N-S, Di Stefano L, Morris EJ, Patel R, White K, et al. (2008) E2F and p53 induce apoptosis independently during Drosophila development but intersect in the context of DNA damage. PLoS Genet 4: e1000153. doi: 10.1371/journal.pgen.1000153 18688282

60. Clemens JC, Worby CA, Simonson-Leff N, Muda M, Maehama T, et al. (2000) Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. Proc Natl Acad Sci USA 97: 6499–6503. 10823906

61. Somma MP, Fasulo B, Cenci G, Cundari E, Gatti M (2002) Molecular dissection of cytokinesis by RNA interference in Drosophila cultured cells. Mol Biol Cell 13: 2448–2460. 12134082

62. Goshima G, Vale RD (2003) The roles of microtubule-based motor proteins in mitosis: comprehensive RNAi analysis in the Drosophila S2 cell line. The Journal of Cell Biology 162: 1003–1016. 12975346

63. Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157: 105–132. 7108955

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 7
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#