Existing users Log In New users Sign up


Akt modes of stem cell regulation: more than meets the eye?

DISCOVERIES (ISSN 2359-7232),2013, October-December

CITATION:
Calautti E. Akt modes of stem cell regulation: more than meets the eye? Discoveries 2013, Oct-Dec; 1(1): e8.
DOI: 10.15190/d.2013.8

Submitted: December 22, 2013; Revised: December 30, 2013; Accepted: December 31, 2013; Published: December 31, 2013; 

GO BACK to 2013, Oct-Dec issue
GO BACK to DISCOVERIES

Akt modes of stem cell regulation: more than meets the eye?


MD, PhD*

Affiliation:
University of Turin, Department of Molecular Biotechnology and Health Sciences, Turin, Italy

*Corresponding author: Enzo Calautti, M.D., Ph.D; Via Nizza 52, 10126 Turin-Italy; Tel: +39-011-6706411; Fax: +39-011-6706432; E- mail: vincenzo.calautti@unito.it


Abstract

Akt signaling regulates many cellular functions that are essential for the proper balance between self-renewal and differentiation of tissue-specific and embryonic stem cells (SCs). However, the roles of Akt and its downstream signaling in SC regulation are rather complex, as Akt activation can either promote SC self-renewal or depletion in a context-dependent manner. In this review we have evidenced three “modes” of Akt-dependent SC regulation, which can be exemplified by three different SC types. In particular, we will discuss: 1) the integration of Akt signaling within the “core” SC signaling circuitry in the maintenance of SC self-renewal and pluripotency (embryonic SCs); 2) quantitative changes in Akt signaling in SC metabolic activity and exit from quiescence (hematopoietic SCs); 3) qualitative changes of Akt signaling in SC regulation: signaling compartment-talization and isoform-specific functions of Akt proteins in SC self-renewal and differentiation (limbal-corneal keratinocyte SCs). These diverse modes of action are not to be intended as mutually exclusive. Rather, it is likely that Akt proteins participate with multiple parallel mechanisms to regulation of the same SC type. We propose that under specific circumstances dictated by distinct developmental stages, differentiation programs or tissue culture conditions, one mode of Akt action prevails over the others in determining SC fates.

Access full text of the manuscript here:

References

1. Weissman IL. Stem cells: units of development, units of regeneration, and units in evolution. Cell. 2000 Jan 7; 100(1): 157-68.
2. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR. A stem cell molecular signature. Science. 2002 Oct 18; 298(5593): 601-4.
3. Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA. "Stemness": transcriptional profiling of embryonic and adult stem cells. Science. 2002 Oct 18; 298(5593): 597-600.
4. Burns CE, Zon LI. Portrait of a stem cell. Dev Cell. 2002 Nov; 3(5): 612-3.
5. Vogel G. Stem cells. 'Stemness' genes still elusive. Science. 2003 Oct 17; 302(5644): 371.
6. Fortunel NO, Otu HH, Ng HH, Chen J, Mu X, Chevassut T, et al. Comment on " 'Stemness': transcriptional profiling of embryonic and adult stem cells" and "a stem cell molecular signature". Science. 2003 Oct 17; 302(5644): 393.
7. Tower J. Stress and stem cells. Wiley Interdiscip Rev Dev Biol. 2012 Nov-Dec; 1(6): 789-802.
8. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6; 153(6): 1194-217.
9. Kenyon CJ. The genetics of ageing. Nature. 2010 Mar 25; 464(7288): 504-12.
10. Eijkelenboom A, Burgering BM. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 2013 Feb; 14(2): 83-97.
11. Plas DR, Thompson CB. Akt-dependent transformation: there is more to growth than just surviving. Oncogene. 2005 Nov 14; 24(50): 7435-42.
12. Robey RB, Hay N. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene. 2006 Aug 7; 25(34): 4683-96.
13. Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012 Jun; 61(6):1315-22.
14. Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science. 2010 Apr 16; 328(5976): 321-6.
15. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 1997 Oct 30; 389(6654): 994-9.
16. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999 Mar 19; 96(6):857-68.
17. Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem. 1999 Jun 11; 274(24): 17184-92.
18. Medema RH, Kops GJ, Bos JL, Burgering BM. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature. 2000 Apr 13; 404(6779):782-7.
19. Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2007 Jun 7; 1(1):101-12.
20. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007 Jan 26; 128(2): 325-39.
21. Renault VM, Rafalski VA, Morgan AA, Salih DA, Brett JO, Webb AE, et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell. 2009 Nov 6; 5(5):527-39.
22. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35.
23. Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell. 2007 Feb; 6(1): 95-110.
24. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003 Dec 11; 426(6967): 620.
25. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16; 460(7253): 392-5.
26. Chen C, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009; 2(98): ra75.
27. Yilmaz OH, Katajisto P, Lamming DW, Gultekin Y, Bauer-Rowe KE, Sengupta S, et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature. 2012 Jun 28; 486(7404): 490-5.
28. Hobbs RM, Seandel M, Falciatori I, Rafii S, Pandolfi PP. Plzf regulates germline progenitor self-renewal by opposing mTORC1. Cell. 2010 Aug 6; 142(3): 468-79.
29. Iglesias-Bartolome R, Patel V, Cotrim A, Leelahavanichkul K, Molinolo AA, Mitchell JB, et al. mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell. 2012 Sep 7; 11(3):401-14.
30. Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell. 2008 Dec 9; 14(6): 458-70.
31. Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, et al. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell. 2010 Apr 20;18(4): 592-604.
32. Khatri S, Yepiskoposyan H, Gallo CA, Tandon P, Plas DR. FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. The Journal of biological chemistry. May 21; 285(21): 15960-5.
33. Gregorian C, Nakashima J, Le Belle J, Ohab J, Kim R, Liu A, et al. Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis. J Neurosci. 2009 Feb 11; 29(6): 1874-86.
34. Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol. 2009 Jun 2; 7(6): e1000121.
35. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006 May 25; 441(7092): 475-82.
36. Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004 Oct 21; 431(7011): 997-1002.
37. Heron-Milhavet L, Khouya N, Fernandez A, Lamb NJ. Akt1 and Akt2: differentiating the aktion. Histol Histopathol. 2011 May; 26(5): 651-62.
38. Gonzalez E, McGraw TE. The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle. 2009 Aug 15; 8(16): 2502-8.
39. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007 Jun 29; 129(7): 1261-74.
40. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005 Feb 18; 307(5712): 1098-101.
41. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006 Dec; 11(6): 859-71.
42. Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell. 2006 Oct;11(4): 583-9.
43. Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J, et al. Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc Natl Acad Sci U S A. 2000 Mar 28; 97(7): 3207-12.
44. Ruvolo PP, Qui YH, Coombes KR, Zhang N, Ruvolo VR, Borthakur G, et al. Low expression of PP2A regulatory subunit B55alpha is associated with T308 phosphorylation of AKT and shorter complete remission duration in acute myeloid leukemia patients. Leukemia. Nov; 25(11): 1711-7.
45. Brognard J, Sierecki E, Gao T, Newton AC. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell. 2007 Mar 23; 25(6): 917-31.
46. Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell. 2007 Apr; 12(4): 487-502.
47. Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008 Sep 18; 27(41): 5527-41.
48. Kandel ES, Skeen J, Majewski N, Di Cristofano A, Pandolfi PP, Feliciano CS, et al. Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage. Mol Cell Biol. 2002 Nov; 22(22): 7831-41.
49. Dummler B, Hemmings BA. Physiological roles of PKB/Akt isoforms in development and disease. Biochem Soc Trans. 2007 Apr; 35(Pt 2): 231-5.
50. Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem. 2001 Oct 19; 276(42): 38349-52.
51. Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 2001 Sep 1; 15(17): 2203-8.
52. Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest. 2003 Jul; 112(2): 197-208.
53. Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, 3rd, et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001 Jun 1; 292(5522): 1728-31.
54. Bottermann K, Reinartz M, Barsoum M, Kotter S, Godecke A. Systematic Analysis Reveals Elongation Factor 2 and alpha-Enolase as Novel Interaction Partners of AKT2. PLoS One. 2013; 8(6): e66045.
55. Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T, et al. Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development. 2005 Jul; 132(13): 2943-54.
56. Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, Ayala R, et al. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res. 2003 Jan 1; 63(1): 196-206.
57. Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009; 11(4): R46.
58. Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, et al. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol. 2005 Dec 19; 171(6): 1023-34.
59. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008 May 16; 133(4): 704-15.
60. Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, et al. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Science signaling. 2009; 2(92): ra62.
61. Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell. 2009 Sep 4; 5(3): 279-89.
62. Teleman AA, Chen YW, Cohen SM. Drosophila Melted modulates FOXO and TOR activity. Dev Cell. 2005 Aug; 9(2): 271-81.
63. Hay N. Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta. Nov; 1813(11): 1965-70.
64. Saoncella S, Tassone B, Deklic E, Avolio F, Jon C, Tornillo G, et al. Nuclear Akt2 opposes limbal keratinocyte stem cell self-renewal by repressing a FOXO-mTORC1 signaling pathway. Stem Cells. 2013 Oct 7.
65. van der Horst A, Burgering BM. Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol. 2007 Jun; 8(6): 440-50.
66. Calnan DR, Brunet A. The FoxO code. Oncogene. 2008 Apr 7; 27(16): 2276-88.
67. van den Berg MC, Burgering BM. Integrating opposing signals toward Forkhead box O. Antioxid Redox Signal. 2011 Feb 15; 14(4): 607-21.
68. Dansen TB, Burgering BM. Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol. 2008 Sep;18(9): 421-9.
69. Bridge D, Theofiles AG, Holler RL, Marcinkevicius E, Steele RE, Martinez DE. FoxO and stress responses in the cnidarian Hydra vulgaris. PLoS One. 2010; 5(7): e11686.
70. Barbet NC, Schneider U, Helliwell SB, Stansfield I, Tuite MF, Hall MN. TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell. 1996 Jan; 7(1): 25-42.
71. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994 Jun 30; 369(6483): 756-8.
72. Pan G, Thomson JA. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 2007 Jan; 17(1): 42-9.
73. Paling NR, Wheadon H, Bone HK, Welham MJ. Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling. J Biol Chem. 2004 Nov 12; 279(46): 48063-70.
74. Watanabe S, Umehara H, Murayama K, Okabe M, Kimura T, Nakano T. Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells. Oncogene. 2006 May 4; 25(19): 2697-707.
75. Storm MP, Bone HK, Beck CG, Bourillot PY, Schreiber V, Damiano T, et al. Regulation of Nanog expression by phosphoinositide 3-kinase-dependent signaling in murine embryonic stem cells. J Biol Chem. 2007 Mar 2; 282(9): 6265-73.
76. Niwa H, Ogawa K, Shimosato D, Adachi K. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature. 2009 Jul 2; 460(7251): 118-22.
77. Silva J, Nichols J, Theunissen TW, Guo G, van Oosten AL, Barrandon O, et al. Nanog is the gateway to the pluripotent ground state. Cell. 2009 Aug 21; 138(4): 722-37.
78. Jeong CH, Cho YY, Kim MO, Kim SH, Cho EJ, Lee SY, et al. Phosphorylation of Sox2 cooperates in reprogramming to pluripotent stem cells. Stem Cells. 2010 Dec; 28(12): 2141-50.
79. Rossant J. Stem cells and early lineage development. Cell. 2008 Feb 22; 132(4): 527-31.
80. Vallier L, Alexander M, Pedersen RA. Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci. 2005 Oct 1; 118(Pt 19): 4495-509.
81. McLean AB, D'Amour KA, Jones KL, Krishnamoorthy M, Kulik MJ, Reynolds DM, et al. Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed. Stem Cells. 2007 Jan; 25(1): 29-38.
82. Singh AM, Reynolds D, Cliff T, Ohtsuka S, Mattheyses AL, Sun Y, et al. Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell. 2012 Mar 2; 10(3): 312-26.
83. Chen CT, Hsu SH, Wei YH. Mitochondrial bioenergetic function and metabolic plasticity in stem cell differentiation and cellular reprogramming. Biochim Biophys Acta. 2012 May; 1820(5): 571-6.
84. Zhang X, Yalcin S, Lee DF, Yeh TY, Lee SM, Su J, et al. FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol. 2011 Sep; 13(9): 1092-9.
85. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature. 2006 May 25; 441(7092):518-22.
86. Li L, Clevers H. Coexistence of quiescent and active adult stem cells in mammals. Science. 2010 Jan 29; 327(5965): 542-5.
87. Snippert HJ, Clevers H. Tracking adult stem cells. EMBO Rep. 2011 Feb; 12(2): 113-22.
88. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A. 2007 Mar 27; 104(13): 5431-6.
89. Hermitte F, Brunet de la Grange P, Belloc F, Praloran V, Ivanovic Z. Very low O2 concentration (0.1%) favors G0 return of dividing CD34+ cells. Stem Cells. 2006 Jan; 24(1): 65-73.
90. Shima H, Takubo K, Tago N, Iwasaki H, Arai F, Takahashi T, et al. Acquisition of G(0) state by CD34-positive cord blood cells after bone marrow transplantation. Exp Hematol. 2010 Dec; 38(12): 1231-40.
91. Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011 Oct 4; 9(4): 298-310.
92. Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood. 2007 Oct 15; 110(8): 3056-63.
93. Owusu-Ansah E, Banerjee U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature. 2009 Sep 24; 461(7263): 537-41.
94. Hsu P, Qu CK. Metabolic plasticity and hematopoietic stem cell biology. Curr Opin Hematol. 2013 Jul; 20(4): 289-94.
95. Hirao A, Hoshii T. Mechanistic / mammalian target protein of rapamycin signaling in hematopoietic stem cells and leukemia. Cancer Sci. 2013 Aug; 104(8): 977-82.
96. Polak R, Buitenhuis M. The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia. Blood. 2012 Jan 26; 119(4): 911-23.
97. Boehm AM, Khalturin K, Anton-Erxleben F, Hemmrich G, Klostermeier UC, Lopez-Quintero JA, et al. FoxO is a critical regulator of stem cell maintenance in immortal Hydra. Proc Natl Acad Sci U S A. 2012 Nov 27; 109(48): 19697-702.
98. Yalcin S, Zhang X, Luciano JP, Mungamuri SK, Marinkovic D, Vercherat C, et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J Biol Chem. 2008 Sep 12; 283(37): 25692-705.
99. Paik JH, Ding Z, Narurkar R, Ramkissoon S, Muller F, Kamoun WS, et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell. 2009 Nov 6; 5(5): 540-53.
100. Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L, et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 2010 Dec 2; 468(7324): 701-4.
101. Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Zheng P. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med. 2008 Sep 29; 205(10): 2397-408.
102. Zon LI. Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature. 2008 May 15; 453(7193): 306-13.
103. Kharas MG, Okabe R, Ganis JJ, Gozo M, Khandan T, Paktinat M, et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood. 2010 Feb 18; 115(7): 1406-15.
104. Juntilla MM, Patil VD, Calamito M, Joshi RP, Birnbaum MJ, Koretzky GA. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood. 2010 May 20; 115(20): 4030-8.
105. Menghini R, Marchetti V, Cardellini M, Hribal ML, Mauriello A, Lauro D, et al. Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: a novel pathway linking obesity to atherosclerosis. Circulation. 2005 Apr 19; 111(15): 1946-53.
106. Kurebayashi Y, Nagai S, Ikejiri A, Ohtani M, Ichiyama K, Baba Y, et al. PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORgamma. Cell Rep. 2012 Apr 19; 1(4): 360-73.
107. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003 May 15; 423(6937): 302-5.
108. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature. 2003 Oct 30; 425(6961): 962-7.
109. Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, Chen CT, et al. Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science. 2005 Oct 14; 310(5746): 306-10.
110. Kalaitzidis D, Sykes SM, Wang Z, Punt N, Tang Y, Ragu C, et al. mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis. Cell Stem Cell. 2012 Sep 7; 11(3): 429-39.
111. Magee JA, Ikenoue T, Nakada D, Lee JY, Guan KL, Morrison SJ. Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. Cell Stem Cell. 2012 Sep 7; 11(3): 415-28.
112. Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, et al. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell. 2010 Apr 20; 18(4): 592-604.
113. Hay N. Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta. 2011 Nov;1813(11):1965-70.
114. Chen JJ, Tseng SC. Corneal epithelial wound healing in partial limbal deficiency. Invest Ophthalmol Vis Sci. 1990 Jul; 31(7): 1301-14.
115. Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell. 1989 Apr 21; 57(2): 201-9.
116. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders. Ophthalmology. 1989 May; 96(5): 709-22;
117. Pellegrini G, Golisano O, Paterna P, Lambiase A, Bonini S, Rama P, et al. Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface. J Cell Biol. 1999 May 17; 145(4): 769-82.
118. Pellegrini G, Rama P, Mavilio F, De Luca M. Epithelial stem cells in corneal regeneration and epidermal gene therapy. J Pathol. 2009 Jan; 217(2): 217-28.
119. Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med. 2010 Jul 8; 363(2): 147-55.
120. Sun TT, Tseng SC, Lavker RM. Location of corneal epithelial stem cells. Nature. 2010 Feb 25; 463(7284): E10-1.
121. Pellegrini G, Traverso CE, Franzi AT, Zingirian M, Cancedda R, De Luca M. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet. 1997 Apr 5; 349(9057): 990-3.
122. Barrandon Y, Green H. Three clonal types of keratinocyte with different capacities for multiplication. Proceedings of the National Academy of Sciences of the United States of America. 1987 Apr; 84(8): 2302-6.
123. De Luca M, Pellegrini G, Green H. Regeneration of squamous epithelia from stem cells of cultured grafts. Regen Med. 2006 Jan; 1(1): 45-57.
124. Lindberg K, Brown ME, Chaves HV, Kenyon KR, Rheinwald JG. In vitro propagation of human ocular surface epithelial cells for transplantation. Invest Ophthalmol Vis Sci. 1993 Aug; 34(9): 2672-9.
125. Ezhkova E, Fuchs E. Regenerative medicine: An eye to treating blindness. Nature. 2010; 466(7306): 567-8.
126. Pellegrini G, Rama P, De Luca M. Vision from the right stem. Trends Mol Med. 2010 Nov 11.
127. Barbaro V, Testa A, Di Iorio E, Mavilio F, Pellegrini G, De Luca M. C/EBPdelta regulates cell cycle and self-renewal of human limbal stem cells. J Cell Biol. 2007 Jun 18; 177(6): 1037-49.
128. Notara M, Alatza A, Gilfillan J, Harris AR, Levis HJ, Schrader S, et al. In sickness and in health: Corneal epithelial stem cell biology, pathology and therapy. Exp Eye Res. 2010 Feb; 90(2): 188-95.
129. Peng H, Katsnelson J, Yang W, Brown MA, Lavker RM. FIH-1/c-kit signaling: a novel contributor to corneal epithelial glycogen metabolism. Invest Ophthalmol Vis Sci. 2013 Apr; 54(4): 2781-6.
130. Martelli AM, Tabellini G, Bressanin D, Ognibene A, Goto K, Cocco L, et al. The emerging multiple roles of nuclear Akt. Biochim Biophys Acta. 2012 Dec; 1823(12): 2168-78.
131. Senoo M, Pinto F, Crum CP, McKeon F. p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell. 2007 May 4; 129(3): 523-36.
132. Barbieri CE, Barton CE, Pietenpol JA. Delta Np63 alpha expression is regulated by the phosphoinositide 3-kinase pathway. The Journal of biological chemistry. 2003 Dec 19; 278(51): 51408-14.
133. Gunschmann C, Stachelscheid H, Akyuz MD, Schmitz A, Missero C, Bruning JC, et al. Insulin/IGF-1 controls epidermal morphogenesis via regulation of FoxO-mediated p63 inhibition. Dev Cell. 2013 Jul 29; 26(2): 176-87.

GO BACK to 2013, Oct-Dec issue
GO BACK to DISCOVERIES
MEET OUR EDITORIAL BOARD
SUBMIT A MANUSCRIPT

Email Email us at info@discoveriesjournals.org if you have any questions.

News & Events Latest news from our journals.

  • 2018 | For Authors!

    PMC highlighted that a high proportion of authors of Discoveries articles are also members of our Editorial Board. As a result, from now on and for at least 1 year, we will only accept articles from authors that are NOT members of Discoveries' Editorial Board. All articles submitted by our members will be immediately rejected until further notice. 

  • 2017-2018 | PubMed inclusion News!

    Discoveries successfully passed the Scientific Quality Review by NLM-NIH for PubMedCentral and PubMed indexing. This is the first and the most important step towards PubMedCentral and PubMed indexing! The second (last) step is the Technical Review.

  • April 2016 | Faster Peer-Review

    Starting on April 13th, all articles selected for a peer-review will receive the post peer-review decision within 10 days. The initial pre-screening time will remain the same (48h from the submission of the manuscript). This decision will significantly accelerate the publication, with no effect on the quality of the peer-review process.

  • February 2016 | Manuscript submission

    Discoveries is commited to excellence, quality and high editorial standards. We are receiving an increasing number of manuscripts for which the identity of the authors/corresponding author can't be verified. Please NOTE that ALL these articles were and will be immediately REJECTED. Indicating an institutional email address is the easiest way to overcome this problem! Moreover, we do not accept any pressure on our editorial board to accept a manuscript. This results in a prompt rejection of the article.

    Editorial Policies
  • January 2016 |Discoveries-AIM

    After reaching all proposed milestones until now (including being indexed by Google Scholar in 2014), Discoveries' next Aim is PubMed indexing of all its articles (already published and upcoming). There will be no charge for the submission or publication of articles in Discoveries before PubMed indexing.

  • August 2015 | Discoveries - on PubMed

    We are happy to announce that our first Discoveries articles were included in PMC and PubMed. More articles (submitted by NIH funded articles) are now processed for being included.

    Discoveries articles now on PubMed
  • April 2015 | Special Issue

    DISCOVERIES publish the SPECIAL ISSUE entitled "INFLAMMATION BETWEEN DEFENSE AND DISEASE: Impact on Tissue Repair and Chronic Sickness".

    Special Issue on "Inflammation"
  • 2015 | Ischemia Collection

    DISCOVERIES launched a call for papers for a Collection of Articles with focus on "ISCHEMIA". If you are interested to submit a manuscript, please contact us at info@discoveriesjournals.org

  • October 2014 | Special Issue

    DISCOVERIES launched a call for papers, for the SPECIAL ISSUE entitled "INFLAMMATION BETWEEN DEFENSE AND DISEASE: Impact on Tissue Repair and Chronic Sickness".

  • September 2014 | Special Issue

    DISCOVERIES just publish the SPECIAL ISSUE entitled "CELL SECRETION & MEMBRANE FUSION" in September 2014. Initially scheduled for publication between October 2014-March 2015, this issue was successfully published earlier than scheduled. 

    Special Issue
  • April 2014 | Indexed by Google Scholar

    All our published articles are now indexed by Google Scholar! Current citations for each individual article published in either Discoveries or Discoveries Reports are also shown. First citations to Discoveries articles are included! Search for the article's title or the authors:

    Google Scholar Search

  • July 2013 | Manuscript Submission

    Submit your manuscript FREE, FAST and EASY ! (in less than 1 minute)
    There are NO fees for the manuscript submission or publishing of the accepted manuscripts.

    Read more

  • July 2013 | DISCOVERIES

    We are now ACCEPTING MANUSCRIPTS for publishing in DISCOVERIES. We aim to publish a small number of high impact experimental articles & reviews (around 40/year) to maintain a high impact factor. Domains of interest: all areas related to Medicine, Biology and Chemistry ...

    Read more

  • July 2013 | DISCOVERIES REPORTS

    We are now ACCEPTING MANUSCRIPTS for DISCOVERIES REPORTS, publishing inovative and important research findings from all areas related to Medicine, Biology and Chemistry. We are also accepting experimental articles that validate/invalidate highly used reagents in current publications (ex. antibodies) and selected articles presenting negative data with impact and of wide scientific interest ...

    Read more

Member Login
Free Registration Click here to sign up
Copyright © 2013 Applied Systems. All Rights Reserved.