Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex

Genes and Development

Volumn 18, Issue 23, 2004, Pages 2893-2904

  Brugarolas, James ^a   Lei, Kui ^b   Hurley, Rebecca L ^c   Manning, Brendan D ^d   Reiling, Jan H ^e   Hafen, Ernst ^e   Witters, Lee A ^c   Ellisen, Leif W ^b   Kaelin Jr , William G ^a,f  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

^c DARTMOUTH MEDICAL SCHOOL   (United States)

^d HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^e UNIVERSITY OF ZURICH   (Switzerland)

^f HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

Hypoxia; mTOR; REDD1 RTP801; TSC1; TSC2; Tuberous Sclerosis Complex

Indexed keywords

ADENYLATE KINASE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CELL PROLIFERATION; CONTROLLED STUDY; DOWN REGULATION; ENERGY TRANSFER; GENE CONTROL; GENE EXPRESSION; GENE FUNCTION; GENE OVEREXPRESSION; GENE TARGETING; HUMAN; HUMAN CELL; HYPOXIA; MOUSE; NONHUMAN; PRIORITY JOURNAL; TUMOR SUPPRESSOR GENE;

3T3 CELLS; ANIMALS; ANOXIA; CELL DIVISION; DOWN-REGULATION; MICE; MICE, INBRED C57BL; PHOSPHORYLATION; PROTEIN KINASES; REPRESSOR PROTEINS; RIBOSOMAL PROTEIN S6 KINASES; RNA, SMALL INTERFERING; TRANSCRIPTION FACTORS; TUMOR SUPPRESSOR PROTEINS;

ANIMALIA; MAMMALIA;

EID: 10044276783     PISSN: 08909369     EISSN: None     Source Type: Journal    
DOI: 10.1101/gad.1256804     Document Type: Article

References (54)

1. Arsham, A.M., Howell, J.J., and Simon, M.C. 2003. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J. Biol. Chem. 278: 29655-29660.
2. Brugarolas, J. and Kaelin, W.G. 2004. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6: 7-10.
3. Brugarolas, J., Vazquez, F., Reddy, A., Sellers, W.R., and Kaelin, W.G. 2003. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4: 147-156.
4. Cantley, L.C. 2002. The phosphoinositide 3-kinase pathway. Science 296: 1655-1657.
5. Carling, D. 2004. The AMP-activated protein kinase cascade - A unifying system for energy control. Trends Biochem. Sci. 29: 18-24.
6. Carsillo, T., Astrinidis, A., and Henske, E.P. 2000. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic lymphangioleiomyomatosis. Proc. Natl. Acad. Sci. 11: 6085-6090.
7. Castro, A.F., Rebhun, J.F., Clark, G.G., and Quilliam, L.A. 2003. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J. Biol. Chem. 278: 32493-32496.
8. Cheadle, J.P., Reeve, M.P., Sampson, J.R., and Kwiatkowski, D.J. 2000. Molecular genetic advances in tuberous sclerosis. Hum. Genet. 107: 97-114.
9. Corradetti, M.N., Inoki, K., Bardeesy, N., DePinho, R.A., and Guan, K.-L. 2004. Regulation of the TSC pathway by LKB1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes & Dev. 18: 1533-1538.
10. Cuaz-Perolin, C., Furman, C., Larigauderie, G., Legedz, L., Lasselin, C., Copin, C., Jaye, M., Searfoss, G., Yu, K.T., Duverger, N., et al. 2004. REDD2 gene is upregulated by modified LDL or hypoxia and mediates human macrophages cell death. Arterioscler. Thromb. Vasc. Biol. 24: 1830-1835.
11. Dan, H.C., Sun, M., Yang, L., Feldman, R.I., Sui, X.M., Ou, C.C., Nellist, M., Yeung, R.S., Halley, D.J., Nicosia, S.V., et al. 2002. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J. Biol. Chem. 277: 35364-35370.
12. Dufner, A. and Thomas, G. 1999. Ribosomal S6 kinase signaling and the control of translation. Exp. Cell Res. 253: 100-109.
13. El-Hashemite, N., Walker, V., Zhang, H., and Kwiatkowski, D.J. 2003. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res. 63: 5173-5177.
14. Ellisen, L.W., Ramsayer, K.D., Johannessen, C.M., Yang, A., Beppu, H., Minda, K., Oliner, J.D., McKeon, F., and Haber, D.A. 2002. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol. Cell 10: 995-1005.
15. Fingar, D.C. and Blenis, J. 2004. Target of rapamycin (TOR): An integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23: 3151-3171.
16. Gao, X. and Pan, D. 2001. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes & Dev. 15: 1383-1392.
17. Gao, X., Zhang, Y., Arrazola, P., Hino, O., Kobayashi, T., Yeung, R.S., Ru, B., and Pan, D. 2002. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat. Cell Biol. 4: 699-704.
18. Garami, A., Zwartkruis, F.J., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S.C., Hafen, E., Bos, J.L., and Thomas, G. 2003. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11: 1457-1466.
19. Gingras, A.C., Raught, B., and Sonenberg, N. 2001. Regulation of translation initiation by FRAP/mTOR. Genes & Dev. 15: 807-826.
20. Hamilton, S.R., Stapleton, D., O'Donnell Jr., J.B., Kung, J.T., Dalal, S.R., Kemp, B.E., and Witters, L.A. 2001. An activating mutation in the γ1 subunit of the AMP-activated protein kinase. FEBS Lett. 500: 163-168.
21. Hawley, S.A., Boudeau, J., Reid, J.L., Mustard, K.L., Udd, L., Makela, T.P., Alessi, D.R., and Hardie, D.G. 2003. Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2: 28.
22. Hudson, C.C., Liu, M., Chiang, G.G., Otterness, D.M., Loomis, D.C., Kaper, F., Giaccia, A.J., and Abraham, R.T. 2002. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell. Biol. 22: 7004-7014.
23. Inoki, K., Li, Y., Zhu, T., Wu, J., and Guan, K.L. 2002, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4: 648-657.
24. Inoki, K., Li, Y., Xu, T., and Guan, K.L. 2003a. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes & Dev. 17: 1829-1834.
25. Inoki, K., Zhu, T., and Guan, K.L. 2003b. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115: 577-590.
26. Jaeschke, A., Hartkamp, J., Saitoh, M., Roworth, W., Nobukuni, T., Hodges, A., Sampson, J., Thomas, G., and Lamb, R. 2002. Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide- 3-OH kinase is mTOR independent. J. Cell Biol. 159: 217-224.
27. Kaelin Jr., W.G. 2002. Molecular basis of the VHL hereditary cancer syndrome. Nat. Rev. Cancer 2: 673-682.
28. Karbowniczek, M., Cash, T., Cheung, M., Robertson, G.P., Astrinidis, A., and Henske, E.P. 2004. Regulation of B-Raf kinase activity by tuberin and Rheb is mTOR independent. J. Biol. Chem. 279: 29930-29937.
29. Kimura, N., Tokunaga, C., Dalal, S., Richardson, C., Yoshino, K., Hara, K., Kemp, B.E., Witters, L.A., Mimura, O., and Yonezawa, K. 2003. A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 8: 65-79.
30. Kwiatkowski, D.J., Zhang, H., Bandura, J.L., Heiberger, K.M., Glogauer, M., el-Hashemite, N., and Onda, H. 2002. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 11: 525-534.
31. Liu, M.Y., Poellinger, L., and Walker, C.L. 2003. Up-regulation of hypoxia-inducible factor 2α in renal cell carcinoma associated with loss of Tsc-2 tumor suppressor gene. Cancer Res. 63: 2675-2680.
32. Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J., and Cantley, L.C. 2002. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10: 151-162.
33. Nguyen-Vu, P.A., Fackler, I., Rust, A., DeClue, J.E., Sander, C.A., Volkenandt, M., Flaig, M., Yeung, R.S., and Wienecke, R. 2001. Loss of tuberin, the tuberous-sclerosis-complex-2 gene product is associated with angiogenesis. J. Cutan. Pathol. 28: 470-475.
34. Pende, M., Um, S.H., Mieulet, V., Sticker, M., Goss, V.L., Mestan, J., Mueller, M., Fumagalli, S., Kozma, S.C., and Thomas, G. 2004. S6K1 (-/-)/S6K2 (-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol. Cell. Biol. 24: 3112-3124.
35. Potter, C.J., Huang, H., and Xu, T. 2001. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105: 357-368.
36. Potter, C.J., Pedraza, L.G., and Xu, T. 2002. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4: 658-665.
37. Reiling, J.H. and Hafen, E. 2004. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes & Dev. (this issue).
38. Rennebeck, G., Kleymenova, E.V., Anderson, R., Yeung, R.S., Artzt, K., and Walker, C.L. 1998. Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc. Natl. Acad. Sci. 95: 15629-15634.
39. Richard, D.E., Berra, E., Gothie, E., Roux, D., and Pouyssegur, J. 1999. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1α) and enhance the transcriptional activity of HIF-1. J. Biol. Chem. 274: 32631-32637.
40. Saucedo, L.J., Gao, X., Chiarelli, D.A., Li, L., Pan, D., and Edgar, B.A. 2003. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat. Cell Biol. 5: 566-571.
41. Scavelli, C., Weber, E., Agliano, M., Cirulli, T., Nico, B., Vacca, A., and Ribatti, D. 2004. Lymphatics at the crossroads of angiogenesis and lymphangiogenesis. J. Anat. 204: 433-449.
42. Semenza, G.L. 2000. HIF-1 and human disease: One highly involved factor. Genes & Dev. 14: 1983-1991.
43. Shaw, R.J., Bardeesy, N., Manning, B.D., Lopez, L., Kostmatka, M., DePinho, R.A., and Cantley, L.C. 2004a. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6: 91-99.
44. Shaw, R.J., Kosmatka, M., Bardeesy, N., Hurley, R.L., Witters, L.A., DePinho, R.A., and Cantley, L.C. 2004b. Inaugural article: The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. 101: 3329-3335.
45. Shoshani, T., Faerman, A., Mett, I., Zelin, E., Tenne, T., Gorodin, S., Moshel, Y., Elbaz, S., Budanov, A., Chajut, A., et al. 2002. Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol. Cell. Biol. 22: 2283-2293.
46. Stocker, H., Radimerski, T., Schindelholz, B., Wittwer, F., Belawat, P., Daram, P., Breuer, S., Thomas, G., and Hafen, E. 2003. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat. Cell Biol. 5: 559-566.
47. Tapon, N., Ito, N., Dickson, B.J., Treisman, J.E., and Hariharan, I.K. 2001. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105: 345-355.
48. Tee, A.R., Manning, B.D., Roux, P.P., Cantley, L.C., and Blenis, J. 2003. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GT-Pase-activating protein complex toward Rheb. Curr. Biol. 13: 1259-1268.
49. Tiainen, M., Ylikorkala, A., and Makela, T.P. 1999. Growth suppression by Lkb1 is mediated by a G (1) cell cycle arrest. Proc. Natl. Acad. Sci. 96: 9248-9251.
50. van Slegtenhorst, M., Nellist, M., Nagelkerken, B., Cheadle, J., Snell, R., van den Ouweland, A., Reuser, A., Sampson, J., Halley, D., and van der Sluijs, P. 1998. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum. Mol. Genet. 7: 1053-1057.
51. Volarevic, S., Stewart, M.J., Ledermann, B., Zilberman, F., Terracciano, L., Montini, E., Grompe, M., Kozma, S.C., and Thomas, G. 2000. Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6. Science 288: 2045-2047.
52. Woods, A., Johnstone, S.R., Dickerson, K., Leiper, F.C., Fryer, L.G., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., and Carling, D. 2003. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13: 2004-2008.
53. Zhang, H., Cicchetti, G., Onda, H., Koon, H.B., Asrican, K., Bajraszewski, N., Vazquez, F., Carpenter, C.L., and Kwiatkowski, D.J. 2003. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J. Clin. Invest. 112: 1223-1233.
54. Zhang, Y., Gao, X., Saucedo, L.J., Ru, B., Edgar, B.A., and Pan, D. 2003. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5: 578-581.