Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2

Genes and Development

Volumn 17, Issue 11, 2003, Pages 1352-1365

  Peng, Xiao ding ^a   Xu, Pei Zhang ^a   Chen, Mei Ling ^a   Hahn Windgassen, Annett ^a   Skeen, Jennifer ^a   Jacobs, Joel ^a   Sundararajan, Deepa ^a   Chen, William S ^a   Crawford, Susan E ^b   Coleman, Kevin G ^c   Hay, Nissim ^a  

^a UNIVERSITY OF ILLINOIS   (United States)

^b NORTHWESTERN UNIVERSITY   (United States)

^c PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

4E BP1; C EBP; FKHR FOXO; mTOR; S6K; TSC2

Indexed keywords

PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PROTEIN KINASE B; SERINE THREONINE KINASE AKT1; SERINE THREONINE KINASE AKT2; SERINE THREONINE KINASE AKT3; SOMATOMEDIN C RECEPTOR; UNCLASSIFIED DRUG;

ADIPOSE TISSUE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE MALFORMATION; CELL DIFFERENTIATION; CELL GROWTH; CELL PROLIFERATION; CELL SIZE; CONGENITAL MALFORMATION; CONTROLLED STUDY; DWARFISM; EMBRYO; ENZYME ACTIVITY; GROWTH RETARDATION; KNOCKOUT MOUSE; MOUSE; MUSCLE ATROPHY; MUSCLE CELL; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; SKIN DISEASE;

ANIMALIA;

EID: 0038624395     PISSN: 08909369     EISSN: None     Source Type: Journal    
DOI: 10.1101/gad.1089403     Document Type: Article

References (62)

1. Altomare, D.A., Guo, K., Cheng, J.Q., Sonoda, G., Walsh, K., and Testa, J.R. 1995. Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene 11: 1055-1060.
2. Altomare, D.A., Lyons, G.E., Mitsuuchi, Y., Cheng, J.Q., and Testa, J.R. 1998. Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin. Oncogene 116: 2407-2411.
3. Barak, Y., Nelson, M.C., Ong, E.S., Jones, Y.Z., Ruiz-Lozano, P., Chien, K.R., Koder, A., and Evans, R.M. 1999. PPAR γ is required for placental, cardiac, and adipose tissue development. Mol. Cell 4: 585-595.
4. Bodine, S.C., Stitt, T.N., Gonzalez, M., Kline, W.O., Stover, G.L., Bauerlein, R., Zlotchenko, E., Scrimgeour, A., Lawrence, J.C., Glass, D.J., et al. 2001. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat. Cell Biol. 3: 1014-1019.
5. Brazil, D.P. and Hemmings, B.A. 2001. Ten years of protein kinase B signalling: A hard Akt to follow. Trends Biochem. Sci. 26: 657-664.
6. Britton, J.S., Lockwood, W.K., Li, L., Cohen, S.M., and Edgar, B.A. 2002. Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev. Cell 2: 239-249.
7. Brodbeck, D., Cron, P., and Hemmings, B.A. 1999. A human protein kinase Bγ with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J. Biol. Chem. 274:9133-9136.
8. Cantley, L.C. and Neel, B.G. 1999. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl. Acad. Sci. 96: 4240-4245.
9. Chen, W.S., Xu, P.Z., Gottlob, K., Chen, M.L., Sokol, K., Shiyanova, T., Roninson, I., Weng, W., Suzuki, R., Tobe, K., et al. 2001. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes & Dev. 15: 2203-2208.
10. Cho, H., Mu, J., Kim, J.K., Thorvaldsen, J.L., Chu, Q., Crenshaw III, E.B., Kaestner, K.H., Bartolomei, M.S., Shulman, G.I., and Birnbaum, M.J. 2001 a. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB β). Science 292: 1728-1731.
11. Cho, H., Thorvaldsen, J.L., Chu, Q., Feng, F., and Birnbaum, M.J. 2001b. Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276:38349-38352.
12. Cong, L.N., Chen, H., Li, Y., Zhou, L., McGibbon, M.A., Taylor, S.I., and Quon, M.J. 1997. Physiological role of Akt in insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. Mol. Endocrinol. 11: 1881-1890.
13. Datta, S.R., Brunet, A., and Greenberg, M.E. 1999. Cellular survival: A play in three Akts. Genes & Dev. 13:2905-2927.
14. Dennis, P.B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S.C., and Thomas, G. 2001. Mammalian TOR: A homeostatic ATP sensor. Science 294:1102-1105.
15. Dufner, A. and Thomas, G. 1999. Ribosomal S6 kinase signaling and the control of translation. Exp. Cell Res. 253: 100-109.
16. Edgar, B.A. 1999. From small flies come big discoveries about size control. Nat. Cell Biol. 1: E191-E193.
17. Fasshauer, M., Klein, J., Kriauciunas, K.M., Ueki, K., Benito, M., and Kahn, C.R. 2001. Essential role of insulin receptor substrate 1 in differentiation of brown adipocytes. Mol. Cell. Biol. 21:319-329.
18. Finch, C.E. and Ruvkun, G. 2001. The genetics of aging. Annu. Rev. Genomics Hum. Genet. 2: 435-462.
19. Fingar, D.C., Salama, S., Tsou, C., Harlow, E., and Blenis, J. 2002. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes & Dev. 16:1472-1487.
20. Gagnon, A., Lau, S., and Sorisky, A. 2001. Rapamycin-sensitive phase of 3T3-L1 preadipocyte differentiation after clonal expansion. J. Cell Physiol. 189:14-22.
21. Garofalo, R.S., Orena, S.J., Rafidi, K., Torchia, A.J., Stock, J.L., Hildebrandt, A.L., Coskran, T., Black, S.C., Brees, D.J., Wicks, J.R., et al. 2003. Mice lacking Akt2/PKβ are growth deficient, lipoatrophic and develop severe diabetes. J. Clin. Invest. (in press).
22. Gingras, A.C., Kennedy, S.G., O'Leary, M.A., Sonenberg, N., and Hay, N. 1998. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes & Dev. 12: 502-513.
23. Gingras, A.C., Gygi, S.P., Raught, B., Polakiewicz, R.D., Abraham, R.T., Hoekstra, M.F., Aebersold, R., and Sonenberg, N. 1999. Regulation of 4E-BP1 phosphorylation: A novel two-step mechanism. Genes & Dev. 13: 1422-1437.
24. Gingras, A.C., Raught, B., and Sonenberg, N. 2001. Regulation of translation initiation by FRAP/mTOR. Genes & Dev. 15: 807-826.
25. Gottlob, K., Majewski, N., Kennedy, S., Kandel, E.S., Robey, R.B., and Hay, N. 2001. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes & Dev. 15: 1406-1418.
26. Hu, E., Tontonoz, P., and Spiegelman, B.M. 1995. Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR γ and C/EBP α. Proc. Natl. Acad. Sci. 92: 9856-9860.
27. 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.
28. Kandel, E.S. and Hay, N. 1999. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell Res. 253: 210-229.
29. 2/M cell cycle checkpoint induced by DNA damage. Mol. Cell. Biol. 22: 7831-7841.
30. Kozma, S.C. and Thomas, G. 2002. Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bioessays 24: 65-71.
31. Kubota, N., Terauchi, Y., Miki, H., Tamemoto, H., Yamauchi, T., Komeda, K., Satoh, S., Nakano, R., Ishii, C., Sugiyama, T., et al. 1999. PPAR γ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol. Cell 4: 597-609.
32. Lawlor, M.A. and Alessi, D.R. 2001. PKB/Akt: A key mediator of cell proliferation, survival and insulin responses? J. Cell Sci. 114: 2903-2910.
33. Liu, J., Baker, J., Perkins, A., Robertson, E., and Efstratiadis, A. 1993. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75: 59-72.
34. Louvi, A., Accili, D., and Efstratiadis, A. 1997. Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev. Biol. 189: 33-48.
35. 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.
36. Menegola, E., Broccia, M.L., and Giavini, E. 2001. Atlas of rat fetal skeleton double stained for bone and cartilage. Teratology 64: 125-133.
37. Miki, H., Yamauchi, T., Suzuki, R., Komeda, K., Tsuchida, A., Kubota, N., Terauchi, Y., Kamon, J., Kaburagi, Y., Matsui, J., et al. 2001. Essential role of insulin receptor substrate 1 (IRS- 1) and IRS-2 in adipocyte differentiation. Mol. Cell. Biol. 21: 2521-2532.
38. Muller, M., Jasmin, J.R., Monteil, R.A., and Loubiere, R. 1991. Embryology of the hair follicle. Early Hum. Dev. 26: 159-166.
39. Nakae, J., Kitamura, T., Kitamura, Y., Biggs, W.H., Arden, K.C., and Accili, D. 2003. The forkhead transcription factor foxol regulates adipocyte differentiation. Dev. Cell 4: 119-129.
40. Nakatani, K., Sakaue, H., Thompson, D.A., Weigel, R.J., and Roth, R.A. 1999. Identification of a human Akt3 (protein kinase B γ) which contains the regulatory serine phosphorylation site. Biochem. Biophys. Res. Commun. 257: 906-910.
41. Pallafacchina, G., Calabria, E., Serrano, A.L., Kalhovde, J.M., and Schiaffino, S. 2002. A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc. Natl. Acad. Sci. 99: 9213-9218.
42. Peng, X.D., Park, S., Gadelha, M.R., Coschigano, K.T., Kopchick, J.J., Frohman, L.A., and Kineman, R.D. 2001. The growth hormone (GH)-axis of GH receptor/binding protein gene-disrupted and metallothionein-human GH-releasing hormone transgenic mice: Hypothalamic neuropeptide and pituitary receptor expression in the absence and presence of GH feedback. Endocrinology 142: 1117-1123.
43. Potter, C.J., Pedraza, L.G., and Xu, T. 2002. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4: 658-665.
44. Radimerski, T., Montagne, J., Rintelen, F., Stocker, H., van Der Kaay, J., Downes, C.P., Hafen, E., and Thomas, G. 2002. dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Nat. Cell Biol. 4: 251-255.
45. Romanelli, A., Dreisbach, V.C., and Blenis, J. 2002. Characterization of phosphatidylinositol 3-kinase-dependent phosphorylation of the hydrophobic motif site Thr389 in p70 S6 kinase 1 (S6K1). J. Biol. Chem. 277: 40281-40289.
46. Rommel, C., Bodine, S.C., Clarke, B.A., Rossman, R., Nunez, L., Stitt, T.N., Yancopoulos, G.D., and Glass, D.J. 2001. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat. Cell Biol. 3: 1009-1013.
47. Ron, D. and Habener, J.F. 1992. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes & Dev. 6: 439-453.
48. Rosen, E.D. and Spiegelman, B.M. 2001. PPARγ: A nuclear regulator of metabolism, differentiation, and cell growth. J. Biol. Chem. 276: 37731-37734.
49. Rosen, E.D., Sarraf, P., Troy, A.E., Bradwin, G., Moore, K., Milstone, D.S., Spiegelman, B.M., and Mortensen, R.M. 1999. PPAR γ is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 4: 611-617.
50. Rosen, E.D., Walkey, C.J., Puigserver, P., and Spiegelman, B.M. 2000. Transcriptional regulation of adipogenesis. Genes & Dev. 14: 1293-1307.
51. Rosen, E.D., Hsu, C.H., Wang, X., Sakai, S., Freeman, M.W., Gonzalez, F.J., and Spiegelman, B.M. 2002. C/EBPα induces adipogenesis through PPARγ: A unified pathway. Genes & Dev. 16: 22-26.
52. Roy, R.R., Monke, S.R., Allen, D.L., and Edgerton, V.R. 1999. Modulation of myonuclear number in functionally overloaded and exercised rat plantaris fibers. J. Appl. Physiol. 87: 634-642.
53. Scanga, S.E., Ruel, L., Binari, R.C., Snow, B., Stambolic, V., Bouchard, D., Peters, M., Calvieri, B., Mak, T.W., Woodgett, J.R., et al. 2000. The conserved PI3′K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila. Oncogene 19: 3971-3977.
54. Shioi, T., McMullen, J.R., Kang, P.M., Douglas, P.S., Obata, T., Franke, T.F., Cantley, L.C., and Izumo, S. 2002. Akt/protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22: 2799-2809.
55. Simpson, L. and Parsons, R. 2001. PTEN: Life as a tumor suppressor. Exp. Cell Res. 264: 29-41.
56. Tanaka, T., Yoshida, N., Kishimoto, T., and Akira, S. 1997. Defective adipocyte differentiation in mice lacking the C/EBPβ and/or C/EBPδ gene. EMBO J. 16: 7432-7443.
57. Tontonoz, P., Hu, E., and Spiegelman, B.M. 1994. Stimulation of adipogenesis in fibroblasts by PPAR γ 2, a lipid-activated transcription factor. Cell 79: 1147-1156.
58. Tuttle, R.L., Gill, N.S., Pugh, W., Lee, J.P., Koeberlein, B., Furth, E.E., Polonsky, K.S., Naji, A., and Birnbaum, M.J. 2001. Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Akt1/PKBα. Nat. Med. 7: 1133-1137.
59. Veis, D.J., Sorenson, C.M., Shutter, J.R., and Korsmeyer, S.J. 1993. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75: 229-240.
60. Verdu, J., Buratovich, M.A., Wilder, E.L., and Birnbaum, M.J. 1999. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nat. Cell Biol. 1: 500-506.
61. Walker, K.S., Deak, M., Paterson, A., Hudson, K., Cohen, P., and Alessi, D.R. 1998. Activation of protein kinase B β and γ isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: Comparison with protein kinase B α. Biochem. J. 331: 299-308.
62. Yeh, W.C., Bierer, B.E., and McKnight, S.L. 1995. Rapamycin inhibits clonal expansion and adipogenic differentiation of 3T3-L1 cells. Proc. Natl. Acad. Sci. 92: 11086-11090.