Regulace syntézy p53

Regulace exprese proteinu p53 je kritická pro kontrolu jeho aktivity v normálních i poškozených buňkách. Velmi dobře je popsána úloha E3 ubikvitin ligázy MDM2, která je za normálních podmínek zodpovědná za degradaci p53 v proteazomu a je esenciální při kontrole aktivity p53 během vývoje organizmu. Nadměrná exprese MDM2 spolu s některými dalšími E3 ligázami podílejícími se rovněž na regulaci stability p53 byla prokázána u řady lidských nádorů, což jen podtrhuje význam posttranslační regulace hladiny proteinu p53. Za stresových podmínek se hladina TP53 na úrovni mRNA zásadně nemění, naopak vše nasvědčuje tomu, že syntéza proteinu p53 je řízena především na úrovni iniciace translace, což představuje významný mechanizmus zodpovědný za kontrolu exprese p53. Na druhou stranu současné práce ukazují, že i TP53 mRNA hraje důležitou roli při regulaci aktivity proteinu p53 v buňce. Proto jsme se v této práci zaměřili a diskutujeme mechanizmy zodpovědné za kontrolu syntézy proteinu p53 a jejich úlohu při regulaci p53 aktivity za normálních podmínek a při různých typech stresu.

Klíčová slova:
syntéza p53 – odpověď na stres – IRES – proteosyntéza – fyziologický stres – RNA-vazebné proteiny

Autoři: A. Ponnuswamy ^1,2; R. Fahraeus ²
Působiště autorů: Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic ¹; Cibles Therapeutiques, INSERM Unité 940, Institut de Génétique Moléculaire, Université Paris 7, Paris, France ²
Vyšlo v časopise: Klin Onkol 2012; 25(Supplementum 2): 32-37

Práce byla podpořena Evropským fondem pro regionální rozvoj a státním rozpočtem České republiky (OP VaVpI – RECAMO, CZ.1.05/2.1.00/03.0101).

Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy.

Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do bi omedicínských časopisů.

Obdrženo: 21. 10. 2012
Přijato: 5. 11. 2012

Souhrn

Klíčová slova:
syntéza p53 – odpověď na stres – IRES – proteosyntéza – fyziologický stres – RNA-vazebné proteiny

Zdroje

1. Hollstein M, Sidransky D, Vogelstein B et al. p53 mutations in human cancers. Science 1991; 253(5015): 49–53.

2. Mitchell SA, Spriggs KA, Bushell M et al. Identification of a motif that mediates polypyrimidine tract-binding protein-dependent internal ribosome entry. Genes Dev 2005; 19(13): 1556–1571.

3. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 2010; 40(2): 310–322.

4. Richter K, Haslbeck M, Buchner J. The heat shock response: life on the verge of death. Mol Cell 2010; 40(2): 253–266.

5. Pan P, van Breukelen F. Preference of IRES-mediated initiation of translation during hibernation in golden-mantled ground squirrels, Spermophilus lateralis. Am J Physiol Regul Integr Comp Physiol 2011; 301(2): R370–377.

6. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 2010; 40(2): 294–309.

7. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell 2010; 40(2): 179–204.

8. Johannes G, Carter MS, Eisen MB et al. Identification of eukaryotic mRNAs that are translated at reduced cap binding complex eIF4F concentrations using a cDNA microarray. Proc Natl Acad Sci U S A 1999; 96(23): 13118–13123.

9. Richter JD, Sonenberg N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 2005; 433(7025): 477–480.

10. Bushell M, Sarnow P. Hijacking the translation apparatus by RNA viruses. J Cell Biol 2002; 158(3): 395–399.

11. Hinnebusch AG. Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 2005; 59: 407–450.

12. Kapasi P, Chaudhuri S, Vyas K et al. L13a blocks 48S assembly: role of a general initiation factor in mRNA-specific translational control. Mol Cell 2007; 25(1): 113–126.

13. Ray PS, Jia J, Yao P et al. A stress-responsive RNA switch regulates VEGFA expression. Nature 2009; 457(7231): 915–919.

14. Holcik M, Sonenberg N, Korneluk RG. Internal ribosome initiation of translation and the control of cell death. Trends Genet 2000; 16(10): 469–473.

15. Leung AK, Sharp PA. MicroRNA functions in stress responses. Mol Cell 2010; 40(1): 205–215.

16. Ewen ME, Miller SJ. p53 and translational control. Biochim Biophys Acta 1996; 1242(3): 181–184.

17. Fu L, Minden MD, Benchimol S. Translational regulation of human p53 gene expression. EMBO J 1996; 15(16): 4392–4401.

18. Chen J, Kastan MB. 5‘-3‘-UTR interactions regulate p53 mRNA translation and provide a target for modulating p53 induction after DNA damage. Genes Dev 2010; 24(19): 2146–2156.

19. Candeias MM, Malbert-Colas L, Powell DJ et al. p53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol 2008; 10(9): 1098–1105.

20. Yin Y, Stephen CW, Luciani MG et al. p53 Stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products. Nat Cell Biol 2002; 4(6): 462–467.

21. Courtois S, Verhaegh G, North S et al. DeltaN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene 2002; 21(44): 6722–6728.

22. Ray PS, Grover R, Das S. Two internal ribosome entry sites mediate the translation of p53 isoforms. EMBO Rep 2006; 7(4): 404–410.

23. Bourougaa K, Naski N, Boularan C et al. Endoplasmic reticulum stress induces G2 cell-cycle arrest via mRNA translation of the p53 isoform p53/47. Mol Cell 2010; 38(1): 78–88.

24. Huez I, Creancier L, Audigier S et al. Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA. Mol Cell Biol 1998; 18(11): 6178–6190.

25. Cornelis S, Bruynooghe Y, Denecker G et al. Identification and characterization of a novel cell cycle-regulated internal ribosome entry site. Mol Cell 2000; 5(4): 597–605.

26. Barraille P, Chinestra P, Bayard F et al. Alternative initiation of translation accounts for a 67/45 kDa dimorphism of the human estrogen receptor ERalpha. Biochem Biophys Res Commun 1999; 257(1): 84–88.

27. Mosner J, Mummenbrauer T, Bauer C et al. Negative feedback regulation of wild-type p53 biosynthesis. EMBO J 1995; 14(18): 4442–4449.

28. Galy B, Creancier L, Prado-Lourenco L et al. p53 directs conformational change and translation initiation blockade of human fibroblast growth factor 2 mRNA. Oncogene 2001; 20(34): 4613–4620.

29. Grover R, Ray PS, Das S. Polypyrimidine tract binding protein regulates IRES-mediated translation of p53 isoforms. Cell Cycle 2008; 7(14): 2189–2198.

30. Grover R, Sharathchandra A, Ponnuswamy A et al. Effect of mutations on the p53 IRES RNA structure: implications for de-regulation of the synthesis of p53 isoforms. RNA Biol 2011; 8(1): 132–142.

31. Kim DY, Kim W, Lee KH et al. hnRNP Q regulates translation of p53 in normal and stress conditions. Cell Death Differ. In press 2012.

32. Takagi M, Absalon MJ, McLure KG et al. Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell 2005; 123(1): 49–63.

33. Kastan MB, Onyekwere O, Sidransky D et al. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991; 51(23 Pt 1): 6304–6311.

34. Fu L, Benchimol S. Participation of the human p53 3‘UTR in translational repression and activation following gamma-irradiation. EMBO J 1997; 16(13): 4117–4125.

35. Mazan-Mamczarz K, Galban S, Lopez de Silanes I et al. RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation. Proc Natl Acad Sci U S A 2003; 100(14): 8354–8359.

36. Yang DQ, Halaby MJ, Zhang Y. The identification of an internal ribosomal entry site in the 5‘-untranslated region of p53 mRNA provides a novel mechanism for the regulation of its translation following DNA damage. Oncogene 2006; 25(33): 4613–4619.

37. Gajjar M, Candeias MM, Malbert-Colas L et al. The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA damage. Cancer Cell 2012; 21(1): 25–35.

38. Ofir-Rosenfeld Y, Boggs K, Michael D et al. Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26. Mol Cell 2008; 32(2): 180–189.

39. Yadavilli S, Mayo LD, Higgins M et al. Ribosomal protein S3: A multi-functional protein that interacts with both p53 and MDM2 through its KH domain. DNA Repair (Amst) 2009; 8(10): 1215–1224.

40. Horn HF, Vousden KH. Cooperation between the ribosomal proteins L5 and L11 in the p53 pathway. Oncogene 2008; 27(44): 5774–5784.

41. Ishizuka A, Siomi MC, Siomi H. A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Genes Dev 2002; 16(19): 2497–2508.

42. Komar AA, Hatzoglou M. Internal ribosome entry sites in cellular mRNAs: mystery of their existence. J Biol Chem 2005; 280(25): 23425–23428.

43. Komar AA, Hatzoglou M. Cellular IRES-mediated translation: the war of ITAFs in pathophysiological states. Cell Cycle 2011; 10(2): 229–240.

44. Lewis SM, Holcik M. For IRES trans-acting factors, it is all about location. Oncogene 2008; 27(8): 1033–1035.

45. Spriggs KA, Bushell M, Mitchell SA et al. Internal ribosome entry segment-mediated translation during apoptosis: the role of IRES-trans-acting factors. Cell Death Differ 2005; 12(6): 585–591.

46. Jacobson MR, Pederson T. Localization of signal recognition particle RNA in the nucleolus of mammalian cells. Proc Natl Acad Sci U S A 1998; 95(14): 7981–7986.

47. Pederson T. The plurifunctional nucleolus. Nucleic Acids Res 1998; 26(17): 3871–3876.

48. Bernardi R, Scaglioni PP, Bergmann S et al. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol 2004; 6(7): 665–672.

49. Poyurovsky MV, Jacq X, Ma C et al. Nucleotide binding by the Mdm2 RING domain facilitates Arf-independent Mdm2 nucleolar localization. Mol Cell 2003; 12(4): 875–887.

50. Borowiec JA, Dean FB, Bullock PA et al. Binding and unwinding – how T antigen engages the SV40 origin of DNA replication. Cell 1990; 60(2): 181–184.

51. Lusetti SL, Cox MM. The bacterial RecA protein and the recombinational DNA repair of stalled replication forks. Annu Rev Biochem 2002; 71(1): 71–100.

52. Fang S, Jensen JP, Ludwig RL et al. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 2000; 275(12): 8945–8951.

53. Xirodimas D, Saville MK, Edling C et al. Different effects of p14ARF on the levels of ubiquitinated p53 and Mdm2 in vivo. Oncogene 2001; 20(36): 4972–4983.