A Mouse Model Uncovers LKB1 as an UVB-Induced DNA Damage Sensor Mediating CDKN1A (p21) Degradation

English version České info

Environmental insults are directly involved in cancer development. In particular, Ultraviolet (UV) radiation has been associated to the acquisition of different types skin cancer and premature skin aging. UV radiation causes modifications in the genetic material of cells (DNA) that if not repaired properly will lead to a mutated DNA (mutated genes) which might trigger the development of cancer. Understanding the molecular basis of the UV-induced DNA damage response is important to elucidate the mechanisms of skin homeostasis and tumorigenesis. Here we provide a UVB-induced skin cancer animal model showing that LKB1 tumor suppressor is also a DNA damage sensor. Importantly, the data suggest that reduced amounts of LKB1 protein in skin could be a risk factor for UV-induced skin carcinogenesis in humans.

Vyšlo v časopise: A Mouse Model Uncovers LKB1 as an UVB-Induced DNA Damage Sensor Mediating CDKN1A (p21) Degradation. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004721
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004721

Souhrn

Zdroje

1. HemminkiA, TomlinsonI, MarkieD, JarvinenH, SistonenP, et al. (1997) Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nat Genet 15: 87–90.

2. ScottKD, Nath-SainS, AgnewMD, MarignaniPA (2007) LKB1 catalytically deficient mutants enhance cyclin D1 expression. Cancer Res 67: 5622–5627.

3. TiainenM, VaahtomeriK, YlikorkalaA, MakelaTP (2002) Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1). Hum Mol Genet 11: 1497–1504.

4. Esteve-PuigR, CanalsF, ColomeN, MerlinoG, RecioJA (2009) Uncoupling of the LKB1-AMPKalpha energy sensor pathway by growth factors and oncogenic BRAF. PLoS One 4: e4771.

5. SpicerJ, AshworthA (2004) LKB1 kinase: master and commander of metabolism and polarity. Curr Biol 14: R383–385.

6. WilliamsT, BrenmanJE (2008) LKB1 and AMPK in cell polarity and division. Trends Cell Biol 18: 193–198.

7. DorfmanJ, MacaraIG (2008) STRAD{alpha} Regulates LKB1 Localization by Blocking Access To Importin-{alpha}, and by Association With Crm1 and Exportin-7. Mol Biol Cell 19: 1614–1626.

8. BoudeauJ, ScottJW, RestaN, DeakM, KielochA, et al. (2004) Analysis of the LKB1-STRAD-MO25 complex. J Cell Sci 117: 6365–6375.

9. LizcanoJM, GoranssonO, TothR, DeakM, MorriceNA, et al. (2004) LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. Embo J 23: 833–843.

10. AlessiDR, SakamotoK, BayascasJR (2006) LKB1-dependent signaling pathways. Annu Rev Biochem 75: 137–163.

11. MehenniH, Lin-MarqN, Buchet-PoyauK, ReymondA, CollartMA, et al. (2005) LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Hum Mol Genet 14: 2209–2219.

12. ZhengB, JeongJH, AsaraJM, YuanYY, GranterSR, et al. (2009) Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell 33: 237–247.

13. SapkotaGP, BoudeauJ, DeakM, KielochA, MorriceN, et al. (2002) Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr336 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz-Jeghers cancer syndrome. Biochem J 362: 481–490.

14. SapkotaGP, DeakM, KielochA, MorriceN, GoodarziAA, et al. (2002) Ionizing radiation induces ataxia telangiectasia mutated kinase (ATM)-mediated phosphorylation of LKB1/STK11 at Thr-366. Biochem J 368: 507–516.

15. UiA, OgiwaraH, NakajimaS, KannoS, WatanabeR, et al. (2013) Possible involvement of LKB1-AMPK signaling in non-homologous end joining. Oncogene 33: 1640–1648.

16. Sanchez-CespedesM, ParrellaP, EstellerM, NomotoS, TrinkB, et al. (2002) Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 62: 3659–3662.

17. JiH, RamseyMR, HayesDN, FanC, McNamaraK, et al. (2007) LKB1 modulates lung cancer differentiation and metastasis. Nature 448: 807–810.

18. Sanchez-CespedesM (2007) A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene 26: 7825–7832.

19. RowanA, BatailleV, MacKieR, HealyE, BicknellD, et al. (1999) Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic malignant melanomas. J Invest Dermatol 112: 509–511.

20. BardeesyN, SinhaM, HezelAF, SignorettiS, HathawayNA, et al. (2002) Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419: 162–167.

21. GurumurthyS, HezelAF, SahinE, BergerJH, BosenbergMW, et al. (2008) LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis. Cancer Res 68: 55–63.

22. LiuW, MonahanKB, PfefferleAD, ShimamuraT, SorrentinoJ, et al. (2012) LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma. Cancer Cell 21: 751–764.

23. Gonzalez-SanchezE, Martin-CaballeroJ, FloresJM, Hernandez-LosaJ, CortesJ, et al. (2013) Lkb1 loss promotes tumor progression of BRAF(V600E)-induced lung adenomas. PLoS One 8: e66933.

24. BendjennatM, BoulaireJ, JascurT, BricknerH, BarbierV, et al. (2003) UV irradiation triggers ubiquitin-dependent degradation of p21(WAF1) to promote DNA repair. Cell 114: 599–610.

25. SoriaG, SperoniJ, PodhajcerOL, PrivesC, GottifrediV (2008) p21 differentially regulates DNA replication and DNA-repair-associated processes after UV irradiation. J Cell Sci 121: 3271–3282.

26. TomS, RanalliTA, PodustVN, BambaraRA (2001) Regulatory roles of p21 and apurinic/apyrimidinic endonuclease 1 in base excision repair. J Biol Chem 276: 48781–48789.

27. UmarA, BuermeyerAB, SimonJA, ThomasDC, ClarkAB, et al. (1996) Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell 87: 65–73.

28. WalshCP, XuGL (2006) Cytosine methylation and DNA repair. Curr Top Microbiol Immunol 301: 283–315.

29. MortusewiczO, SchermellehL, WalterJ, CardosoMC, LeonhardtH (2005) Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci U S A 102: 8905–8909.

30. FotedarR, BendjennatM, FotedarA (2004) Role of p21WAF1 in the cellular response to UV. Cell Cycle 3: 134–137.

31. AbbasT, SivaprasadU, TeraiK, AmadorV, PaganoM, et al. (2008) PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Genes Dev 22: 2496–2506.

32. NishitaniH, ShiomiY, IidaH, MichishitaM, TakamiT, et al. (2008) CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation. J Biol Chem 283: 29045–29052.

33. ChenX, ChiY, BloecherA, AebersoldR, ClurmanBE, et al. (2004) N-acetylation and ubiquitin-independent proteasomal degradation of p21(Cip1). Mol Cell 16: 839–847.

34. LeeH, ZengSX, LuH (2006) UV Induces p21 rapid turnover independently of ubiquitin and Skp2. J Biol Chem 281: 26876–26883.

35. MansillaSF, SoriaG, VallergaMB, HabifM, Martinez-LopezW, et al. (2013) UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability. Nucleic Acids Res 41: 6942–6951.

36. NoonanFP, OtsukaT, BangS, AnverMR, MerlinoG (2000) Accelerated ultraviolet radiation-induced carcinogenesis in hepatocyte growth factor/scatter factor transgenic mice. Cancer Res 60: 3738–3743.

37. RecioJA, MerlinoG (2003) Hepatocyte growth factor/scatter factor induces feedback up-regulation of CD44v6 in melanoma cells through Egr-1. Cancer Res 63: 1576–1582.

38. RecioJA, NoonanFP, TakayamaH, AnverMR, DurayP, et al. (2002) Ink4a/arf deficiency promotes ultraviolet radiation-induced melanomagenesis. Cancer Res 62: 6724–6730.

39. SoriaG, PodhajcerO, PrivesC, GottifrediV (2006) P21Cip1/WAF1 downregulation is required for efficient PCNA ubiquitination after UV irradiation. Oncogene 25: 2829–2838.

40. PrivesC, GottifrediV (2008) The p21 and PCNA partnership: a new twist for an old plot. Cell Cycle 7: 3840–3846.

41. EllerMS, MaedaT, MagnoniC, AtwalD, GilchrestBA (1997) Enhancement of DNA repair in human skin cells by thymidine dinucleotides: evidence for a p53-mediated mammalian SOS response. Proc Natl Acad Sci U S A 94: 12627–12632.

42. MortonJP, JamiesonNB, KarimSA, AthineosD, RidgwayRA, et al. (2010) LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology 139: 586–597, 597 e581–586.

43. ZengPY, BergerSL (2006) LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate transcriptional activation. Cancer Res 66: 10701–10708.

44. WolffH, HartlA, EilkenHM, HadianK, ZieglerM, et al. (2006) Live-cell assay for simultaneous monitoring of expression and interaction of proteins. Biotechniques 41: 688, 690, 692.

45. HouX, LiuJE, LiuW, LiuCY, LiuZY, et al. (2011) A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation. Oncogene 30: 2933–2942.

46. UiA, OgiwaraH, NakajimaS, KannoS, WatanabeR, et al. (2014) Possible involvement of LKB1-AMPK signaling in non-homologous end joining. Oncogene 33: 1640–1648.

47. AllanLA, FriedM (1999) p53-dependent apoptosis or growth arrest induced by different forms of radiation in U2OS cells: p21WAF1/CIP1 repression in UV induced apoptosis. Oncogene 18: 5403–5412.

48. NaumannU, WellerM (1998) Retroviral BAX gene transfer fails to sensitize malignant glioma cells to CD95L-induced apoptosis and cancer chemotherapy. Int J Cancer 77: 645–648.

49. PolyakK, WaldmanT, HeTC, KinzlerKW, VogelsteinB (1996) Genetic determinants of p53-induced apoptosis and growth arrest. Genes Dev 10: 1945–1952.

50. ChinL, HahnWC, GetzG, MeyersonM (2011) Making sense of cancer genomic data. Genes Dev 25: 534–555.

51. ArmstrongBK, KrickerA (2001) The epidemiology of UV induced skin cancer. J Photochem Photobiol B 63: 8–18.

52. SancarA, Lindsey-BoltzLA, Unsal-KacmazK, LinnS (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73: 39–85.

53. AbbasT, DuttaA (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9: 400–414.

54. VassarR, CoulombePA, DegensteinL, AlbersK, FuchsE (1991) Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease. Cell 64: 365–380.

55. Andreu-PerezP, Esteve-PuigR, de Torre-MinguelaC, Lopez-FauquedM, Bech-SerraJJ, et al. (2011) Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. Sci Signal 4: ra58.

56. ShinY, LiuJ, ChangJH, ExarhosGJ (2002) Sustained drug release on temperature-responsive poly(N-isopropylacrylamide)-integrated hydroxyapatite. Chem Commun (Camb) 1718–1719.

57. ColomeN, ColladoJ, Bech-SerraJJ, LiivI, AntonLC, et al. (2010) Increased apoptosis after autoimmune regulator expression in epithelial cells revealed by a combined quantitative proteomics approach. J Proteome Res 9: 2600–2609.