Translational Upregulation of an Individual p21 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress

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Cells sense nutrient levels in their environment in order to determine if conditions are favorable to divide. GCN2 is a protein that senses amino acids and responds to amino acid deficiency by suppressing protein synthesis and increasing the expression of genes involved in recovery from nutrient stress. Although GCN2’s role in amino acid sensing is well-characterized, it is not known how it links nutrient availability with the cell cycle. Here, we show that GCN2 induces the cell cycle inhibitor p21Cip1 at the level of protein translation. The induction of p21 is limited to a specific messenger RNA variant that contains upstream open reading frames, and these upstream open reading frames are required for its enhanced translation under stress. Previously, the functional significance of these different p21 variants was unknown. Upregulation of p21 allows cells to halt division and survive under conditions of nutrient stress. Collectively, this work demonstrates a new mechanism of p21 regulation and the connection between GCN2 and the cell cycle.

Vyšlo v časopise: Translational Upregulation of an Individual p21 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005212
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005212

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Zdroje

1. Shackelford RE, Kaufmann WK, Paules RS (1999) Cell cycle control, checkpoint mechanisms, and genotoxic stress. Environ Health Perspect 107 Suppl 1: 5–24. 10229703

2. Jung YS, Qian Y, Chen X (2010) Examination of the expanding pathways for the regulation of p21 expression and activity. Cell Signal 22: 1003–1012. doi: 10.1016/j.cellsig.2010.01.013 20100570

3. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, et al. (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825. 8242752

4. El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, et al. (1994) WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54: 1169–1174. 8118801

5. Kivinen L, Tsubari M, Haapajarvi T, Datto MB, Wang XF, et al. (1999) Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1-binding sites. Oncogene 18: 6252–6261. 10597223

6. Huang L, Sowa Y, Sakai T, Pardee AB (2000) Activation of the p21WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) through the Sp1 sites. Oncogene 19: 5712–5719. 11126357

7. Joseph B, Orlian M, Furneaux H (1998) p21(waf1) mRNA contains a conserved element in its 3'-untranslated region that is bound by the Elav-like mRNA-stabilizing proteins. J Biol Chem 273: 20511–20516. 9685407

8. Wang W, Furneaux H, Cheng H, Caldwell MC, Hutter D, et al. (2000) HuR regulates p21 mRNA stabilization by UV light. Mol Cell Biol 20: 760–769. 10629032

9. Lu Z, Hunter T (2010) Ubiquitylation and proteasomal degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK inhibitors. Cell Cycle 9: 2342–2352. 20519948

10. Child ES, Mann DJ (2006) The intricacies of p21 phosphorylation: protein/protein interactions, subcellular localization and stability. Cell Cycle 5: 1313–1319. 16775416

11. Gartel AL, Radhakrishnan SK, Serfas MS, Kwon YH, Tyner AL (2004) A novel p21WAF1/CIP1 transcript is highly dependent on p53 for its basal expression in mouse tissues. Oncogene 23: 8154–8157. 15361845

12. Radhakrishnan SK, Gierut J, Gartel AL (2006) Multiple alternate p21 transcripts are regulated by p53 in human cells. Oncogene 25: 1812–1815. 16261158

13. Sood R, Porter AC, Olsen DA, Cavener DR, Wek RC (2000) A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha. Genetics 154: 787–801. 10655230

14. Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34: 7–11. 16246168

15. Vattem KM, Wek RC (2004) Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A 101: 11269–11274. 15277680

16. Lu PD, Harding HP, Ron D (2004) Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol 167: 27–33. 15479734

17. Leung-Pineda V, Pan Y, Chen H, Kilberg MS (2004) Induction of p21 and p27 expression by amino acid deprivation of HepG2 human hepatoma cells involves mRNA stabilization. Biochem J 379: 79–88. 14715082

18. Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, et al. (2010) The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J 29: 2082–2096. doi: 10.1038/emboj.2010.81 20473272

19. Maalouf M, Alphonse G, Colliaux A, Beuve M, Trajkovic-Bodennec S, et al. (2009) Different mechanisms of cell death in radiosensitive and radioresistant p53 mutated head and neck squamous cell carcinoma cell lines exposed to carbon ions and x-rays. Int J Radiat Oncol Biol Phys 74: 200–209. doi: 10.1016/j.ijrobp.2009.01.012 19362238

20. Koritzinsky M, Magagnin MG, van den Beucken T, Seigneuric R, Savelkouls K, et al. (2006) Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. The EMBO Journal 25: 1114–1125. 16467844

21. Kaul G, Pattan G, Rafeequi T (2011) Eukaryotic elongation factor-2 (eEF2): its regulation and peptide chain elongation. Cell Biochem Funct 29: 227–234. doi: 10.1002/cbf.1740 21394738

22. Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci U S A 97: 12625–12630. 11035797

23. Hamanaka RB, Bennett BS, Cullinan SB, Diehl JA (2005) PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell 16: 5493–5501. 16176978

24. Braun F, Bertin-Ciftci J, Gallouet AS, Millour J, Juin P (2011) Serum-nutrient starvation induces cell death mediated by Bax and Puma that is counteracted by p21 and unmasked by Bcl-x(L) inhibition. PLoS One 6: e23577. doi: 10.1371/journal.pone.0023577 21887277

25. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, et al. (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 15: 481–490. doi: 10.1038/ncb2738 23624402

26. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, et al. (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11: 619–633. 12667446

27. Zhou D, Palam LR, Jiang L, Narasimhan J, Staschke KA, et al. (2008) Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem 283: 7064–7073. doi: 10.1074/jbc.M708530200 18195013

28. Palam LR, Baird TD, Wek RC (2011) Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J Biol Chem 286: 10939–10949. doi: 10.1074/jbc.M110.216093 21285359

29. Lee YY, Cevallos RC, Jan E (2009) An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation. J Biol Chem 284: 6661–6673. doi: 10.1074/jbc.M806735200 19131336

30. Baird TD, Palam LR, Fusakio ME, Willy JA, Davis CM, et al. (2014) Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKalpha. Mol Biol Cell 25: 1686–1697. doi: 10.1091/mbc.E14-02-0704 24648495

31. Raveh-Amit H, Maissel A, Poller J, Marom L, Elroy-Stein O, et al. (2009) Translational control of protein kinase Ceta by two upstream open reading frames. Mol Cell Biol 29: 6140–6148. doi: 10.1128/MCB.01044-09 19797084

32. Martin R, Berlanga JJ, de Haro C (2013) New roles of the fission yeast eIF2alpha kinases Hri1 and Gcn2 in response to nutritional stress. J Cell Sci 126: 3010–3020. doi: 10.1242/jcs.118067 23687372

33. Tvegård T, Soltani H, Skjølberg HC, Krohn M, Nilssen EA, et al. (2007) A novel checkpoint mechanism regulating the G1/S transition. Genes & Development 21: 649–654. 17369398

34. Grewe M, Gansauge F, Schmid RM, Adler G, Seufferlein T (1999) Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res 59: 3581–3587. 10446965

35. Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S, Mercep L, et al. (1998) Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem 273: 14424–14429. 9603954

36. Kawamata S, Sakaida H, Hori T, Maeda M, Uchiyama T (1998) The upregulation of p27Kip1 by rapamycin results in G1 arrest in exponentially growing T-cell lines. Blood 91: 561–569. 9427710

37. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, et al. (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18: 283–293. 15866171

38. Daga RR, Bolanos P, Moreno S (2003) Regulated mRNA stability of the Cdk inhibitor Rum1 links nutrient status to cell cycle progression. Curr Biol 13: 2015–2024. 14653990

39. Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49: 6449–6465. 2684393

40. Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9: 400–414. doi: 10.1038/nrc2657 19440234

41. Johannes G, Sarnow P (1998) Cap-independent polysomal association of natural mRNAs encoding c-myc, BiP, and eIF4G conferred by internal ribosome entry sites. RNA 4: 1500–1513. 9848649