Loss of thymidine kinase 1 inhibits lung cancer growth and metastatic attributes by reducing GDF15 expression


Autoři: Parmanand Malvi aff001;  Radoslav Janostiak aff002;  Arvindhan Nagarajan aff002;  Guoping Cai aff002;  Narendra Wajapeyee aff001
Působiště autorů: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America aff001;  Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America aff002
Vyšlo v časopise: Loss of thymidine kinase 1 inhibits lung cancer growth and metastatic attributes by reducing GDF15 expression. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008439
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008439

Souhrn

Metabolic alterations that are critical for cancer cell growth and metastasis are one of the key hallmarks of cancer. Here, we show that thymidine kinase 1 (TK1) is significantly overexpressed in tumor samples from lung adenocarcinoma (LUAD) patients relative to normal controls, and this TK1 overexpression is associated with significantly reduced overall survival and cancer recurrence. Genetic knockdown of TK1 with short hairpin RNAs (shRNAs) inhibits both the growth and metastatic attributes of LUAD cells in culture and in mice. We further show that transcriptional overexpression of TK1 in LUAD cells is driven, in part, by MAP kinase pathway in a transcription factor MAZ dependent manner. Using targeted and gene expression profiling-based approaches, we then show that loss of TK1 in LUAD cells results in reduced Rho GTPase activity and reduced expression of growth and differentiation factor 15 (GDF15). Furthermore, ectopic expression of GDF15 can partially rescue TK1 knockdown-induced LUAD growth and metastasis inhibition, confirming its important role as a downstream mediator of TK1 function in LUAD. Collectively, our findings demonstrate that TK1 facilitates LUAD tumor and metastatic growth and represents a target for LUAD therapy.

Klíčová slova:

Adenocarcinoma of the lung – Gene expression – Immunoblot analysis – Lung and intrathoracic tumors – Metastasis – Metastatic tumors – Secondary lung tumors – Squamous cell lung carcinoma


Zdroje

1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367–80. Epub 2008/09/26. doi: 10.1056/NEJMra0802714 18815398.

2. de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res. 2018;7(3):220–33. Epub 2018/07/28. doi: 10.21037/tlcr.2018.05.06 30050761; PubMed Central PMCID: PMC6037963.

3. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54. Epub 2018/01/25. doi: 10.1038/nature25183 29364287.

4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. Epub 2011/03/08. doi: 10.1016/j.cell.2011.02.013 21376230.

5. Pavlova NN, Thompson CB. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016;23(1):27–47. Epub 2016/01/16. doi: 10.1016/j.cmet.2015.12.006 26771115; PubMed Central PMCID: PMC4715268.

6. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703–7. Epub 2008/09/09. doi: 10.1016/j.cell.2008.08.021 18775299.

7. Vander Heiden MG, DeBerardinis RJ. Understanding the Intersections between Metabolism and Cancer Biology. Cell. 2017;168(4):657–69. Epub 2017/02/12. doi: 10.1016/j.cell.2016.12.039 28187287; PubMed Central PMCID: PMC5329766.

8. Nagarajan A, Malvi P, Wajapeyee N. Oncogene-directed alterations in cancer cell metabolism. Trends Cancer. 2016;2(7):365–77. Epub 2016/11/09. doi: 10.1016/j.trecan.2016.06.002 27822561; PubMed Central PMCID: PMC5096652.

9. Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, et al. Metabolic Heterogeneity in Human Lung Tumors. Cell. 2016;164(4):681–94. Epub 2016/02/09. doi: 10.1016/j.cell.2015.12.034 26853473; PubMed Central PMCID: PMC4752889.

10. Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, et al. Lactate Metabolism in Human Lung Tumors. Cell. 2017;171(2):358–71 e9. Epub 2017/10/07. doi: 10.1016/j.cell.2017.09.019 28985563; PubMed Central PMCID: PMC5684706.

11. Sohoni S, Ghosh P, Wang T, Kalainayakan SP, Vidal C, Dey S, et al. Elevated heme synthesis and uptake underpin intensified oxidative metabolism and tumorigenic functions in non-small cell lung cancer cells. Cancer Res. 2019. Epub 2019/03/25. doi: 10.1158/0008-5472.CAN-18-2156 30902795.

12. Kim J, Hu Z, Cai L, Li K, Choi E, Faubert B, et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature. 2017;546(7656):168–72. Epub 2017/05/26. doi: 10.1038/nature22359 28538732; PubMed Central PMCID: PMC5472349.

13. Sellers K, Fox MP, Bousamra M, 2nd, Slone SP, Higashi RM, Miller DM, et al. Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J Clin Invest. 2015;125(2):687–98. Epub 2015/01/22. doi: 10.1172/JCI72873 25607840; PubMed Central PMCID: PMC4319441.

14. Galan-Cobo A, Sitthideatphaiboon P, Qu X, Poteete A, Pisegna MA, Tong P, et al. LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS-Mutant Lung Adenocarcinoma. Cancer Res. 2019;79(13):3251–67. Epub 2019/05/02. doi: 10.1158/0008-5472.CAN-18-3527 31040157; PubMed Central PMCID: PMC6606351.

15. Singh A, Ruiz C, Bhalla K, Haley JA, Li QK, Acquaah-Mensah G, et al. De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer. FASEB J. 2018:fj201800204. Epub 2018/06/16. doi: 10.1096/fj.201800204 29906244; PubMed Central PMCID: PMC6219836.

16. Wang Y, Jiang X, Wang S, Yu H, Zhang T, Xu S, et al. Serological TK1 predict pre-cancer in routine health screenings of 56,178 people. Cancer Biomark. 2018;22(2):237–47. Epub 2018/04/25. doi: 10.3233/CBM-170846 29689706.

17. Wei YT, Luo YZ, Feng ZQ, Huang QX, Mo AS, Mo SX. TK1 overexpression is associated with the poor outcomes of lung cancer patients: a systematic review and meta-analysis. Biomark Med. 2018;12(4):403–13. Epub 2018/03/27. doi: 10.2217/bmm-2017-0249 29575921.

18. Wang Y, Jiang X, Dong S, Shen J, Yu H, Zhou J, et al. Serum TK1 is a more reliable marker than CEA and AFP for cancer screening in a study of 56,286 people. Cancer Biomark. 2016;16(4):529–36. Epub 2016/03/24. doi: 10.3233/CBM-160594 27002755.

19. Weagel EG, Burrup W, Kovtun R, Velazquez EJ, Felsted AM, Townsend MH, et al. Membrane expression of thymidine kinase 1 and potential clinical relevance in lung, breast, and colorectal malignancies. Cancer Cell Int. 2018;18:135. Epub 2018/09/15. doi: 10.1186/s12935-018-0633-9 30214377; PubMed Central PMCID: PMC6131957.

20. Okamura S, Osaki T, Nishimura K, Ohsaki H, Shintani M, Matsuoka H, et al. Thymidine kinase-1/CD31 double immunostaining for identifying activated tumor vessels. Biotech Histochem. 2019;94(1):60–4. Epub 2018/10/16. doi: 10.1080/10520295.2018.1499962 30317880.

21. Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A. 2001;98(24):13790–5. Epub 2001/11/15. doi: 10.1073/pnas.191502998 11707567; PubMed Central PMCID: PMC61120.

22. Okayama H, Kohno T, Ishii Y, Shimada Y, Shiraishi K, Iwakawa R, et al. Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. Cancer Res. 2012;72(1):100–11. Epub 2011/11/15. doi: 10.1158/0008-5472.CAN-11-1403 22080568.

23. Selamat SA, Chung BS, Girard L, Zhang W, Zhang Y, Campan M, et al. Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression. Genome Res. 2012;22(7):1197–211. Epub 2012/05/23. doi: 10.1101/gr.132662.111 22613842; PubMed Central PMCID: PMC3396362.

24. Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, et al. Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A. 2001;98(24):13784–9. Epub 2001/11/15. doi: 10.1073/pnas.241500798 11707590; PubMed Central PMCID: PMC61119.

25. Stearman RS, Dwyer-Nield L, Zerbe L, Blaine SA, Chan Z, Bunn PA Jr., et al. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol. 2005;167(6):1763–75. Epub 2005/11/30. doi: 10.1016/S0002-9440(10)61257-6 16314486; PubMed Central PMCID: PMC1613183.

26. Su LJ, Chang CW, Wu YC, Chen KC, Lin CJ, Liang SC, et al. Selection of DDX5 as a novel internal control for Q-RT-PCR from microarray data using a block bootstrap re-sampling scheme. BMC Genomics. 2007;8:140. Epub 2007/06/02. doi: 10.1186/1471-2164-8-140 17540040; PubMed Central PMCID: PMC1894975.

27. Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439(7074):353–7. Epub 2005/11/08. doi: 10.1038/nature04296 16273092.

28. Hou J, Aerts J, den Hamer B, van Ijcken W, den Bakker M, Riegman P, et al. Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PLoS One. 2010;5(4):e10312. Epub 2010/04/28. doi: 10.1371/journal.pone.0010312 20421987; PubMed Central PMCID: PMC2858668.

29. Gyorffy B, Surowiak P, Budczies J, Lanczky A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One. 2013;8(12):e82241. Epub 2013/12/25. doi: 10.1371/journal.pone.0082241 24367507; PubMed Central PMCID: PMC3867325.

30. Lee ES, Son DS, Kim SH, Lee J, Jo J, Han J, et al. Prediction of recurrence-free survival in postoperative non-small cell lung cancer patients by using an integrated model of clinical information and gene expression. Clin Cancer Res. 2008;14(22):7397–404. Epub 2008/11/18. doi: 10.1158/1078-0432.CCR-07-4937 19010856.

31. Westbrook TF, Martin ES, Schlabach MR, Leng Y, Liang AC, Feng B, et al. A genetic screen for candidate tumor suppressors identifies REST. Cell. 2005;121(6):837–48. Epub 2005/06/18. doi: 10.1016/j.cell.2005.03.033 15960972.

32. Lin L, Chamberlain L, Pak ML, Nagarajan A, Gupta R, Zhu LJ, et al. A large-scale RNAi-based mouse tumorigenesis screen identifies new lung cancer tumor suppressors that repress FGFR signaling. Cancer Discov. 2014;4(10):1168–81. Epub 2014/07/13. doi: 10.1158/2159-8290.CD-13-0747 25015643; PubMed Central PMCID: PMC4184919.

33. Hsu F, De Caluwe A, Anderson D, Nichol A, Toriumi T, Ho C. Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations. Curr Oncol. 2017;24(4):228–33. Epub 2017/09/07. doi: 10.3747/co.24.3496 28874890; PubMed Central PMCID: PMC5576458.

34. Burotto M, Chiou VL, Lee JM, Kohn EC. The MAPK pathway across different malignancies: a new perspective. Cancer. 2014;120(22):3446–56. Epub 2014/06/21. doi: 10.1002/cncr.28864 24948110; PubMed Central PMCID: PMC4221543.

35. Loots GG, Ovcharenko I. rVISTA 2.0: evolutionary analysis of transcription factor binding sites. Nucleic Acids Res. 2004;32(Web Server issue):W217–21. Epub 2004/06/25. doi: 10.1093/nar/gkh383 15215384; PubMed Central PMCID: PMC441521.

36. Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18(2):333–4. Epub 2002/02/16. doi: 10.1093/bioinformatics/18.2.333 11847087.

37. McAllister KA, Yasseen AA, McKerr G, Downes CS, McKelvey-Martin VJ. FISH comets show that the salvage enzyme TK1 contributes to gene-specific DNA repair. Front Genet. 2014;5:233. Epub 2014/08/26. doi: 10.3389/fgene.2014.00233 25152750; PubMed Central PMCID: PMC4126492.

38. Chen YL, Eriksson S, Chang ZF. Regulation and functional contribution of thymidine kinase 1 in repair of DNA damage. J Biol Chem. 2010;285(35):27327–35. Epub 2010/06/18. doi: 10.1074/jbc.M110.137042 20554529; PubMed Central PMCID: PMC2930731.

39. Skovgaard T, Rasmussen LJ, Munch-Petersen B. Thymidine kinase 1 deficient cells show increased survival rate after UV-induced DNA damage. Nucleosides Nucleotides Nucleic Acids. 2010;29(4–6):347–51. Epub 2010/06/15. doi: 10.1080/15257771003741091 20544518.

40. Mariotti LG, Pirovano G, Savage KI, Ghita M, Ottolenghi A, Prise KM, et al. Use of the gamma-H2AX assay to investigate DNA repair dynamics following multiple radiation exposures. PLoS One. 2013;8(11):e79541. Epub 2013/12/07. doi: 10.1371/journal.pone.0079541 24312182; PubMed Central PMCID: PMC3843657.

41. Eriksson M, Uhlin U, Ramaswamy S, Ekberg M, Regnstrom K, Sjoberg BM, et al. Binding of allosteric effectors to ribonucleotide reductase protein R1: reduction of active-site cysteines promotes substrate binding. Structure. 1997;5(8):1077–92. Epub 1997/08/15. doi: 10.1016/s0969-2126(97)00259-1 9309223.

42. Hofer A, Ekanem JT, Thelander L. Allosteric regulation of Trypanosoma brucei ribonucleotide reductase studied in vitro and in vivo. J Biol Chem. 1998;273(51):34098–104. Epub 1998/12/16. doi: 10.1074/jbc.273.51.34098 9852067.

43. Chimploy K, Mathews CK. Mouse ribonucleotide reductase control: influence of substrate binding upon interactions with allosteric effectors. J Biol Chem. 2001;276(10):7093–100. Epub 2000/12/02. doi: 10.1074/jbc.M006232200 11099495.

44. Mathews CK. Deoxyribonucleotide metabolism, mutagenesis and cancer. Nat Rev Cancer. 2015;15(9):528–39. Epub 2015/08/25. doi: 10.1038/nrc3981 26299592.

45. Bar-Sagi D, Hall A. Ras and Rho GTPases: a family reunion. Cell. 2000;103(2):227–38. Epub 2000/11/01. doi: 10.1016/s0092-8674(00)00115-x 11057896.

46. Sahai E, Marshall CJ. RHO-GTPases and cancer. Nat Rev Cancer. 2002;2(2):133–42. Epub 2003/03/15. doi: 10.1038/nrc725 12635176.

47. Benitah SA, Valeron PF, van Aelst L, Marshall CJ, Lacal JC. Rho GTPases in human cancer: an unresolved link to upstream and downstream transcriptional regulation. Biochim Biophys Acta. 2004;1705(2):121–32. Epub 2004/12/14. doi: 10.1016/j.bbcan.2004.10.002 15588766.

48. Sadok A, Marshall CJ. Rho GTPases: masters of cell migration. Small GTPases. 2014;5:e29710. Epub 2014/07/01. doi: 10.4161/sgtp.29710 24978113; PubMed Central PMCID: PMC4107589.

49. Vogiatzi F, Brandt DT, Schneikert J, Fuchs J, Grikscheit K, Wanzel M, et al. Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5. Proc Natl Acad Sci U S A. 2016;113(52):E8433–E42. Epub 2016/12/14. doi: 10.1073/pnas.1612711114 27956623; PubMed Central PMCID: PMC5206569.

50. Boutin AT, Liao WT, Wang M, Hwang SS, Karpinets TV, Cheung H, et al. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer. Genes Dev. 2017;31(4):370–82. Epub 2017/03/16. doi: 10.1101/gad.293449.116 28289141; PubMed Central PMCID: PMC5358757.

51. Rao F, Xu J, Fu C, Cha JY, Gadalla MM, Xu R, et al. Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1. Proc Natl Acad Sci U S A. 2015;112(6):1773–8. Epub 2015/01/27. doi: 10.1073/pnas.1424642112 25617365; PubMed Central PMCID: PMC4330756.

52. Liang Y, Xu X, Wang T, Li Y, You W, Fu J, et al. The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis. Cell Death Dis. 2017;8(7):e2928. Epub 2017/07/14. doi: 10.1038/cddis.2017.325 28703807; PubMed Central PMCID: PMC5550870.

53. Conley-LaComb MK, Saliganan A, Kandagatla P, Chen YQ, Cher ML, Chinni SR. PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling. Mol Cancer. 2013;12(1):85. Epub 2013/08/02. doi: 10.1186/1476-4598-12-85 23902739; PubMed Central PMCID: PMC3751767.

54. Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature. 1990;348(6297):125–32. Epub 1990/11/08. doi: 10.1038/348125a0 2122258.

55. John J, Frech M, Wittinghofer A. Biochemical properties of Ha-ras encoded p21 mutants and mechanism of the autophosphorylation reaction. J Biol Chem. 1988;263(24):11792–9. Epub 1988/08/25. 3042780.

56. Feuerstein J, Goody RS, Wittinghofer A. Preparation and characterization of nucleotide-free and metal ion-free p21 "apoprotein". J Biol Chem. 1987;262(18):8455–8. Epub 1987/06/25. 3298232.

57. Zhang B, Zhang Y, Wang Z, Zheng Y. The role of Mg2+ cofactor in the guanine nucleotide exchange and GTP hydrolysis reactions of Rho family GTP-binding proteins. J Biol Chem. 2000;275(33):25299–307. Epub 2000/06/14. doi: 10.1074/jbc.M001027200 10843989.

58. Kim DK, Kim EK, Jung DW, Kim J. Cytoskeletal alteration modulates cancer cell invasion through RhoA-YAP signaling in stromal fibroblasts. PLoS One. 2019;14(3):e0214553. Epub 2019/03/29. doi: 10.1371/journal.pone.0214553 30921404; PubMed Central PMCID: PMC6438594.

59. Cao J, Yang T, Tang D, Zhou F, Qian Y, Zou X. Increased expression of GEF-H1 promotes colon cancer progression by RhoA signaling. Pathol Res Pract. 2019;215(5):1012–9. Epub 2019/03/09. doi: 10.1016/j.prp.2019.02.008 30846413.

60. Moynahan ME, Cui TY, Jasin M. Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 2001;61(12):4842–50. Epub 2001/06/19. 11406561.

61. Hodge JC, Bub J, Kaul S, Kajdacsy-Balla A, Lindholm PF. Requirement of RhoA activity for increased nuclear factor kappaB activity and PC-3 human prostate cancer cell invasion. Cancer Res. 2003;63(6):1359–64. Epub 2003/03/22. 12649199.

62. Liu N, Bi F, Pan Y, Sun L, Xue Y, Shi Y, et al. Reversal of the malignant phenotype of gastric cancer cells by inhibition of RhoA expression and activity. Clin Cancer Res. 2004;10(18 Pt 1):6239–47. Epub 2004/09/28. doi: 10.1158/1078-0432.CCR-04-0242 15448013.

63. Charalampous KD, Askew WE. Cerebellar cAMP levels following acute and chronic morphine administration. Can J Physiol Pharmacol. 1977;55(1):117–20. Epub 1977/02/01. doi: 10.1139/y77-017 191170.

64. de Jager SC, Bermudez B, Bot I, Koenen RR, Bot M, Kavelaars A, et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp Med. 2011;208(2):217–25. Epub 2011/01/19. doi: 10.1084/jem.20100370 21242297; PubMed Central PMCID: PMC3039852.

65. Ratnam NM, Peterson JM, Talbert EE, Ladner KJ, Rajasekera PV, Schmidt CR, et al. NF-kappaB regulates GDF-15 to suppress macrophage surveillance during early tumor development. J Clin Invest. 2017;127(10):3796–809. Epub 2017/09/12. doi: 10.1172/JCI91561 28891811; PubMed Central PMCID: PMC5617672.

66. Windrichova J, Fuchsova R, Kucera R, Topolcan O, Fiala O, Finek J, et al. MIC1/GDF15 as a Bone Metastatic Disease Biomarker. Anticancer Res. 2017;37(3):1501–5. Epub 2017/03/21. doi: 10.21873/anticanres.11477 28314325.

67. Duan L, Pang HL, Chen WJ, Shen WW, Cao PP, Wang SM, et al. The role of GDF15 in bone metastasis of lung adenocarcinoma cells. Oncol Rep. 2019;41(4):2379–88. Epub 2019/03/01. doi: 10.3892/or.2019.7024 30816507.

68. Zhao C, Li Y, Qiu W, He F, Zhang W, Zhao D, et al. C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation. Oncogene. 2018;37(35):4821–37. Epub 2018/05/19. doi: 10.1038/s41388-018-0298-9 29773900; PubMed Central PMCID: PMC6117268.

69. Gazin C, Wajapeyee N, Gobeil S, Virbasius CM, Green MR. An elaborate pathway required for Ras-mediated epigenetic silencing. Nature. 2007;449(7165):1073–7. Epub 2007/10/26. doi: 10.1038/nature06251 17960246; PubMed Central PMCID: PMC2147719.

70. Ren XD, Kiosses WB, Schwartz MA. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J. 1999;18(3):578–85. Epub 1999/02/02. doi: 10.1093/emboj/18.3.578 9927417; PubMed Central PMCID: PMC1171150.

71. Ding S, Wu X, Li G, Han M, Zhuang Y, Xu T. Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell. 2005;122(3):473–83. Epub 2005/08/13. doi: 10.1016/j.cell.2005.07.013 16096065.

Štítky
Genetika Reprodukční medicína

Článek vyšel v časopise

PLOS Genetics


2019 Číslo 10

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Léčba bolesti v ordinaci praktického lékaře
nový kurz
Autoři: MUDr. PhDr. Zdeňka Nováková, Ph.D.

Revmatoidní artritida: včas a k cíli
Autoři: MUDr. Heřman Mann

Jistoty a nástrahy antikoagulační léčby aneb kardiolog - neurolog - farmakolog - nefrolog - právník diskutují
Autoři: doc. MUDr. Štěpán Havránek, Ph.D., prof. MUDr. Roman Herzig, Ph.D., doc. MUDr. Karel Urbánek, Ph.D., prim. MUDr. Jan Vachek, MUDr. et Mgr. Jolana Těšínová, Ph.D.

Léčba akutní pooperační bolesti
Autoři: doc. MUDr. Jiří Málek, CSc.

Nové antipsychotikum kariprazin v léčbě schizofrenie
Autoři: prof. MUDr. Cyril Höschl, DrSc., FRCPsych.

Všechny kurzy
Kurzy Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se