The molecular mechanisms that underlie the tumor suppressor function of LKB1

Acta Biochimica et Biophysica Sinica

Volumn 41, Issue 2, 2009, Pages 97-107

  Fan, Dahua ^a   Ma, Chao ^a   Zhang, Haitao ^a  

^a GUANGDONG MEDICAL UNIVERSITY   (China)

Author keywords

LKB1; lung adenocarcinoma; Peutz Jeghers syndrome; tumor suppressor

Indexed keywords

PROTEIN SERINE THREONINE KINASE; STK11 PROTEIN, HUMAN;

APOPTOSIS; CELL POLARITY; CELL PROLIFERATION; ENZYMOLOGY; GENETICS; HUMAN; LUNG TUMOR; MUTATION; PEUTZ JEGHERS SYNDROME; PHYSIOLOGY; REVIEW; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR GENE;

APOPTOSIS; CELL POLARITY; CELL PROLIFERATION; GENES, TUMOR SUPPRESSOR; HUMANS; LUNG NEOPLASMS; MUTATION; PEUTZ-JEGHERS SYNDROME; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION;

EID: 64249128769     PISSN: 16729145     EISSN: 17457270     Source Type: Journal    
DOI: 10.1093/abbs/gmn011     Document Type: Review

References (108)

1. Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A and Bignell G, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998, 391: 184-187.
2. Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R and Müller O, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 1998, 18: 38-43.
3. Peutz JL. A very remarkable case of familial polyposis of the mucous membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentation of the skin and mucous membranes. Ned Tijdschr Geneeskd 1921, 10: 134-146.
4. Jeghers H, McKusic VA and Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lip, and digits: a syndrome of diagnostic significance. N Engl J Med 1949, 241: 1031-1036.
5. Nafz J, Arce JD, Fleig V, Patzelt A, Mazurek S and Rosl F. Interference with energy metabolism by 5-aminoimidazole-4-carboxamide-l-β-D- ribofuranoside induces HPV suppression in cervical carcinoma cells and apoptosis in the absence of LKB1. Biochem J 2007,403: 501-510.
6. Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P and Torrice C, et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 2007, 448: 807-810.
7. Fenton H, Carlile B, Montgomery EA, Carraway H, Herman J, Sahin F and Su GH, et al. LKB1 protein expression in human breast cancer. Appl Immunohistochem Mol Morphol 2006, 14: 146-153.
8. Dowling RJ, Zakikhaui M, Fantus IG, Pollak M and Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 2007, 67: 10804-10812.
9. Carretero J, Medina PP, Blanco R, Smit L, Tang M, Roncador G and Maestre L, et al. Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Oncogene 2007, 26: 1616-1625.
10. Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJ and Keller JJ, et al. Frequency and spectrum of cancers in the Peutz - Jeghers syndrome. Clin Cancer Res 2006, 12: 3209-3215.
11. Mehenni H, Gehrig C, Nezu J, Oku A, Shimane M, Rossier C and Guex N, et al. Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet 1998,63: 1641-1650.
12. Ylikorkala A, Avizienyte E, Tomlinson IP, Tiainen M, Roth S, Loukola A and Hemminki A, et al. Mutations and impaired function of LKB1 in familial and non-familial Peutz - Jeghers syndrome and a sporadic testicular cancer. Hum Mol Genet 1999, 8: 45-51.
13. Westerman AM, Entius MM, Boor PP, Koole R, de Baar E, Offerhaus GJ and Lubinski J, et al. Novel mutations in the LKB1/STK11 gene in Dutch Peutz - Jeghers families. Hum Mutat 1999, 13: 476-481.
14. Volikos E, Robinson J, Aittomaki K, Mecklin JP, Järvinen H, Westerman AM and de Rooji FW, et al. LKB1 exonic and whole gene deletions are a common cause of Peutz - Jeghers syndrome. J Med Genet 2006, 43: pel8.
15. Hearle N, Rudd MF, Lim W, Murday V, Lim AG, Phillips RK and Lee PW, et al. Exonic STK11 deletions are not a rare cause of Peutz-Jeghers syndrome. J Med Genet 2006, 43: pel5.
16. Aretz S, Stienen D, Uhlhaas S, Loff S, Back W, Pagenstecher C and McLeod DR, et al. High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 2005, 26: 513-519.
17. de Leng WW, Jansen M, Carvalho R, Polak M, Musler AR, Milne AN and Keller JJ, et al. Genetic defects underlying Peutz - Jeghers syndrome (PJS) and exclusion of the polarity-associated MARK/Parl gene family as potential PJS candidates. Clin Genet 2007, 72: 568-573.
18. Forbes S, Clements J, Dawson E, Bamford S, Webb T, Dogan A and Flanagan A, et al. COSMIC 2005. Br J Cancer 2006, 94: 318-322.
19. Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM and Westra WH, et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 2002, 62: 3659-3662.
20. Carretero J, Medina PP, Pio R, Montuenga LM and Sanchez-Cespedes M. Novel and natural knockout lung cancer cell lines for the LKB1/ STK11 tumor suppressor gene. Oncogene 2004, 23: 4037-4040.
21. Avizienyte E, Loukola A, Roth S, Hemminki A, Tarkkanen M, Salovaara R and Arola J, et al. LKB1 somatic mutations in sporadic tumors. Am J Pathol 1999, 154: 677-681.
22. Nakau M, Miyoshi H, Seldin MF, Imamura M, Oshima M and Taketo MM. Hepatocellular carcinoma caused by loss of heterozygosity in Lkbl gene knockout mice. Cancer Res 2002, 62: 4549-4553.
23. Zhong D, Guo L, de Aguirre I, Liu X, Lamb N, Sun SY and Gal AA, et al. LKB1 mutation in large cell carcinoma of the lung. Lung Cancer 2006, 53: 285-294.
24. Trojan J, Brieger A, Raedle J, Esteller M and Zeuzem S. 5'-CpG island methylation of the LKB 1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer. Gut 2000, 47: 272-276.
25. Esteller M, Avizienyte E, Corn PG, Lothe RA, Baylin SB, Aaltonen LA and Herman JG. Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz - Jeghers syndrome. Oncogene 2000, 19: 164-168.
26. Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC and Westerman AM, et al. Germline and somatic mutations of the STK11/LKB1 Peutz - Jeghers gene in pancreatic and biliary cancers. Am J Pathol 1999, 154: 1835-1840.
27. Lizcano JM, Göransson O, Toth R, Deak M, Morrice NA, Boudeau J and Hawley SA, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 2004, 23: 833-843.
28. Benton R and St Johnston D. Drosophila PAR-1 and 14-3-3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells. Cell 2003, 115: 691-704.
29. Cohen D, Brennwald PJ, Rodriguez-Boulau E and Müsch A. Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton. J Cell Biol 2004, 164: 717-727.
30. Kahn BB, Alquier T, Carling D and Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 2005, 1: 15-25.
31. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA and Montminy M, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005, 310: 1642-1646.
32. Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M and Kondo S, et al. The energy sensing LKB1 - AMPK pathway regulates p27(kipl) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 2007, 9: 218-224.
33. Hemminki A. The molecular basis and clinical aspects of Peutz-Jeghers syndrome. Cell Mol Life Sci 1999, 55: 735-750.
34. Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ and Clevers HC. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 2004, 116: 457-466.
35. Sanders MJ, Grondin PO, Hegarty BD, Snowden MA and Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 2007, 403: 139-148.
36. Hurov JB, Huang M, White LS, Lennerz J, Choi CS, Cho YR and Kim HJ, el al. Loss of the Par-lb/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo. Proc Natl Acad Sci USA 2007, 104: 5680-5685.
37. Marignani PA, Kanai F and Carpenter CL. LKB1 associates with Brgl and is necessary for Brgl-induced growth arrest. J Biol Chem 2001, 276:32415-32418.
38. Alessi DR, Sakamoto K and Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem 2006, 75: 137-163.
39. Su JY, Erikson E and Mailer JL. Cloning and characterization of a novel serine/threonine protein kinase expressed in early Xenopus embryos. J Biol Chem 1996, 271: 14430-14437.
40. Smith DP, Spicer J, Smith A, Swift S and Ashworth A. The mouse Peutz - Jeghers syndrome gene Lkbl encodes a nuclear protein kinase. Hum Mol Genet 1999, 8: 1479-1485.
41. Watts JL, Morton DG, Bestman J and Kemphues KJ. The C. elegans par-4 gene encodes a putative serine - threonine kinase required for establishing embryonic asymmetry. Development 2000, 127: 1467-1475.
42. Martin SG and St Johnston D. A role for Drosophila LKB1 in anterior - posterior axis formation and epithelial polarity. Nature 2003, 421: 379-384.
43. Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P and Agarwala R, et al. Initial sequencing and comparative analysis of the mouse genome. Nature 2002, 420: 560-562.
44. Boudeau J, Sapkota G and Alessi DR. LKBL a protein kinase regulating cell proliferation and polarity. FEBS Lett 2003, 546: 159-165.
45. Jishage K, Nezu J, Kawase Y, Iwata T, Watanabe M, Miyoshi A and Ose A, et al. Role of Lkbl, the causative gene of Peutz - Jegher's syndrome, in embryogenesis and polyposis. Proc Natl Acad Sci USA 2002, 99: 8903-8908.
46. Rowan A, Churchman M, Jefferey R, Hanby A, Poulsom R and Tomlinson I. In situ analysis of LKB1/STK11 mRNA expression in human normal tissues and tumours. J Pathol 2000, 192: 203-206.
47. Ylikorkala A, Rossi DJ, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M and Mäkelä TP. Vascular abnormalities and deregulation of VEGF in Lkbl-deficient mice. Science 2001, 293: 1323-1326.
48. Yoo LI, Chung DC and Yuan J. LKBl - a master tumour suppressor of the small intestine and beyond. Nat Rev Cancer 2002, 2: 529-535.
49. Conde E, Suarez-Gauthier A, García-García E, Lopez-Rios F, Lopez-Encuentra A, García-Lujan R and Morente M, et al. Specific pattern of LKB1 and phospho-acetyl-CoA carboxylase protein immunostaining in human normal tissues and lung carcinomas. Hum Pathol 2007,38: 1351-1360.
50. Sapkota GP, Kieloch A, Lizcano JM, Lain S, Arthur JS, Williams MR and Morrice N, et al. Phosphorylation of the protein kinase mutated in Peutz - Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-depeudeut protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth. J Biol Chem. 2001, 276: 19469-19482.
51. Barnes AP, Lilley BN, Pan YA, Plummer LJ, Powell AW, Raines AN and Sanes JR, et al. LKB] and SAD kinases define a pathway required for the polarization of cortical neurons. Cell 2007, 129: 549-563.
52. Shelly M, Cancedda L, Heilshorn S, Sumbre G and Poo MM. LKB1/ STRAD promotes axon initiation during neuronal polarization. Cell 2007, 129: 565-577.
53. Sapkota GP, Boudeau J, Deak M, Kieloch A, Morrice N and Alessi DR. Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr.3.36 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz - Jeghers cancer syndrome. Biochem J 2002, 362:481-490.
54. Boudeau J, Baas AF, Deak M, Morrice NA, Kieloch A, Schutkowski M and Prescott AR, et al. MO25α/β interact with STRADα/β enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J 2003, 22: 5102-5114.
55. Collins SP, Reoma JL, Gamm DM and Uhler MD. LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem J 2000, 345: 673-680.
56. Scott JW, Norman DG, Hawley SA, Kontogiannis L and Hardie DG. Protein kinase substrate recognition studied using the recombinant catalytic domain of AMP-activated protein kinase and a model substrate. J Mol Biol 2002, 317: 309-323.
57. Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA and Alessi DR, et al. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J 2003, 22: 3062-3072.
58. Boudeau J, Scott JW, Resta N, Deak M, Kieloch A, Komauder D and Hardie DG, et al. Analysis of the LKB1 - STRAD - MO25 complex. J Cell Sci 2004, 117: 6365-6375.
59. Milburn CC, Boudeau J, Deak M, Alessi DR and van Aalten DM. Crystal structure of MO25α in complex with the C terminus of the pseudo kinase STE20-related adaptor. Nat Struct Mol Biol 2004, 11: 193-200.
60. Dorfman J and Macara IG. STRADα regulates LKB1 localization by blocking access to importin-α, and by association with Crml and exportin-7. Mol Biol Cell 2008, 19: 1614-1626.
61. Kau TR, Way JC and Silver PA. Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer 2004, 4: 106-117.
62. Terry LJ, Shows EB and Wente SR. Crossing the nuclear envelope: hierarchical regulation of uucleocytoplasmic transport. Science 2007, 318: 1412-1416.
63. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002, 2: 442-454.
64. Kemphues KJ, Priess JR, Morton DG and Cheng NS. Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 1988, 52: 311-320.
65. Morton DG, Roos JM and Kemphues KJ. par-4, a gene required for cytoplasmic localization and determination of specific cell types in Caenorhabditis elegans embryogenesis. Genetics 1992, 1.30: 771 -790.
66. Kusakabe M and Nishida E. The polarity-inducing kinase Par-1 controls Xenopus gastrulatiou in cooperation with 14-3-3 and aPKC. EMBO J 2004, 23: 4190-4201.
67. Bayraktar J, Zygmuut D and Carthew RW. Par-1 kinase establishes cell polarity and functions in Notch signaling in the Drosophila embryo. J Cell Sci 2006, 119: 711-721.
68. Betschinger J, Mechtler K and Knoblich JA. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 2003, 422: 326-330.
69. Drewes G. MARKing tau for tangles and toxicity. Trends Biochem Sci 2004, 29: 548-555.
70. Kishi M, Pan YA, Crump JG and Sanes JR. Mammalian SAD kinases are required for neuronal polarization. Science 2005, 307: 929-932.
71. Crump JG, Zhen M, Jin Y and Bargmann CI. The SAD-1 kinase regulates presynaptic vesicle clustering and axon termination. Neuron 2001,29: 115-129.
72. Hung W, Hwang C, Po MD and Zhen M. Neuronal polarity is regulated by a direct interaction between a scaffolding protein, Neurabin, and a presynaptic SAD-1 kinase in Caenorhabditis elegans. Development 2007, 134: 237-249.
73. Lee TH, Koh H, Kim M, Kim Y, Lee SY, Karess RE and Lee SH, et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 2007, 447: 1017-1020.
74. Mirouse V, Swick LL, Kazgan N, St Johnston D and Brenman JE. LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J Cell Biol 2007, 177: 387-392.
75. Zhang S, Schafer-Hales K, Khuri FR, Zhou W, Vertino PM and Marcus AI The tumor suppressor LKB1 regulates lung cancer cell polarity by mediating cdc42 recruitment and activity. Cancer Res 2008, 68: 740-748.
76. Etienne-Manneville S. Cdc42 - the centre of polarity. J Cell Sci 2004, 117: 1291-1300.
77. Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem 2003, 72: 743-781.
78. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Mäkelä TP and Alessi DR, et al. Complexes between the LKB1 tumor suppressor, STRADαβ and MO25αβ are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003, 2: 28.
79. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA and Cantley LC. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 2004, 101: 3329-3335.
80. Sakamoto K, McCarthy A, Smith D, Green KA, Grahame Hardie D, Ashworth A and Alessi DR. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J 2005, 24: 1810-1820.
81. Hardie DG and Sakamoto K. AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda) 2006, 21: 48-60.
82. Hardie DG, Scott JW, Pan DA and Hudson ER. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 2003,546: 113 - 120.
83. Hayashi T, Hirshman MF, Kurth EJ, Winder WW and Goodyear LJ. Evidence for 5'AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 1998, 47: 1369-1373.
84. Winder WW and Hardie DG. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol 1996, 270: 299-304.
85. Ruderman NB, Saha AK, Vavvas D and Witters LA. Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol 1999, 276: El-El8.
86. Koh HJ, Arnolds DE, Fujii N, Trail TT, Rogers MJ, Jessen N and Li Y, ei al. Skeletal muscle-selective knockout of LKB1 increases insulin sensitivity, improves glucose homeostasis, and decreases TRB3. Mol Cell Biol 2006, 26: 8217-8227.
87. Thomson DM, Brown JD, Fillmore N, Condon BM, Kim HJ, Barrow JR and Winder WW. LKB1 and the regulation of malonyl-CoA and fatty acid oxidation in muscle. Am J Physiol Endocrinol Metab 2007, 293: 1572-1579.
88. Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S and Hedrick S, et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 2005, 437: 1109 -1111.
89. Bolster DR, Crazier SJ, Kimball SR and Jefferson LS. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 2002, 277: 23977-23980.
90. Carling D. AMP-activated protein kinase: balancing the scales. Biochimie 2005, 87: 87-91.
91. Corradetti MN, Inoki K, Bardeesy N, DePinho RA and Guan KL. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz - Jeghers syndrome. Genes Dev 2004, 18: 1533-1538.
92. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA and Cantley LC. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004, 6: 91-99.
93. Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M and Mäkelä TP. The LKB1 tumor suppressor kinase in human disease. Biochim Biophys Acta 2007, 1775: 63-75.
94. Tiainen M, Ylikorkala A and Mäkelä TP. Growth suppression by Lkbl is mediated by a G(l) cell cycle arrest. Proc Natl Acad Sci USA 1999,96: 9248-9251.
95. Qiu W, Schönleben F, Thaker HM, Goggins M and Su GH. A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma. Oncogene 2006, 25: 2937-2942.
96. Xie X, Wang Z and Chen Y. Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kipl) induction. Mol Cell Biochem 2007, 301: 115-122.
97. Bardeesy N, Sinha M, Hezel AF, Signoretti S, Hathaway NA, Sharpless NE and Loda M, et al. Loss of the Lkbl tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 2002, 419: 162-167.
98. Tiainen M, Vaahtomeri K, Ylikorkala A and Mäkelä TP. Growth arrest by the LKB1 tumor suppressor: induction of p21(WAFT/CIPl). Hum Mol Genet 2002, 11: 1497-1504.
99. Zeng PY and Berger SL. LKB1 is recruited to the p21/WAFl promoter by p53 to mediate transcriptional activation. Cancer Res 2006, 66: 10701-10708.
100. Setogawa T, Shinozaki-Yabana S, Masuda T, Matsuura K and Akiyama T. The tumor suppressor LKB1 induces p21 expression in collaboration with LMO4, GATA-6, and Ldbl. Biochem Biophys Res Commun 2006, 343: 1186-1190.
101. Scott KD, Nath-Sain S, Agnew MD and Marignani PA. LKB1 cataly-tically deficient mutants enhance cyclin Dl expression. Cancer Res 2007, 67: 5622-5627.
102. Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R and Brien TP, ei al. The Peutz - Jegher gene product LKB1 is a mediator of p53-depeudent cell death. Mol Cell 2001, 7: 1307-1319.
103. Adachi-Yamada T, Fujimura-Kamada K, Nishida Y and Matsumoto K. Distortion of proximodistal information causes JNK-dependent apoptosis in Drosophila wing. Nature 1999, 400: 166-169.
104. Lee JH, Koh H, Kim M, Park J, Lee SY, Lee S and Chung J. JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila. Cell Death Differ 2006, 13: 1110-1122.
105. Lee JH, Lee E, Park J, Kim E, Kim J and Chung J. In vivo p53 function is indispensable for DNA damage-induced apoptotic signaling in Drosophila. FEBS Lett 2003, 550: 5-10.
106. Mukherjee P, Mulrooney TJ, Marsh J, Blair D, Chiles TC and Seyfried TN. Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain. Mol Cancer 2008, 7: 37.
107. Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL and McBumie W, et al. Important role of the LKB1 - AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 2008, 412: 211-221.
108. Liu J, Hu T and Hou X. High-level expression of functional tumor suppressor LKB1 in Escherichia coli. Acta Biochim Biophys Sin 2007, 39: 779-786.