Neuroprotection Signaling of Nuclear Akt in Neuronal Cells

다국어 초록 (Multilingual Abstract)

Akt is one of the central kinases that perform a pivotal function in mediating survival signaling in a wide range of neuronal cell typesin response to growth factor stimulation. The recent findings of a number of targets for Akt suggest that it prohibits neuronal deathby both impinging on the cytoplasmic cell death machinery and by regulating nuclear proteins. The presence of active Akt in thenuclei of mammalian cells is no longer debatable, and this has been corroborated by the finding of multiple targets in the nucleus ofPC12 cells. However, it is also clear that the nuclear Akt signaling exists independent of the cytosolic Akt signaling, thereby showinga distinctive feature of nuclear Akt signaling as opposed to its cytosolic counterpart. The principal objective of this review is tosummarize our current state of knowledge regarding nuclear Akt signaling in neuronal survival, and to introduce current theoriesregarding the roles of nuclear Akt in neuron.

참고문헌 (Reference)

1 Itahana K, "Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation" 12 : 1151-1164, 2003

2 Brunet A, "Transcriptiondependent and-independent control of neuronal survival by the PI3K-Akt signaling pathway" 11 : 297-305, 2001

3 Borgatti P, "Threonine 308 phosphorylated form of Akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin" 196 : 79-88, 2003

4 Ahmed NN, "The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential" 8 : 1957-1963, 1993

5 Franke TF, "The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase" 81 : 727-736, 1995

6 Nicholson KM, "The protein kinase B/Akt signalling pathway in human malignancy" 14 : 381-395, 2002

7 Brazil DP, "Ten years of protein kinase B signalling : a hard Akt to follow" 26 : 657-664, 2001

8 Villa P, "Synthesis of specific proteins in trophic factor-deprived neurons undergoing apoptosis" 62 : 1468-1475, 1994

9 Liu X, "Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival" 104 : 9679-9684, 2007

10 Monie TP, "Structural insights into the transcriptional and translational roles of Ebp1" 26 : 3936-3944, 2007

11 Tokuyama Y, "Specific phosphorylation of nucleophosmin on Thr(199)by cyclin-dependent kinase 2-cyclin E and its role in centrosome duplication" 276 : 21529-21537, 2001

12 Grisendi S, "Role of nucleophosmin in embryonic development and tumorigenesis" 437 : 147-153, 2005

13 Lee SB, "Ribosomal protein S3, a new substrate of Akt, serves as a signal mediator between neuronal apoptosis and DNA repair" 285 : 29457-29468, 2010

14 Cardone MH, "Regulation of cell death protease caspase-9 by phosphorylation" 282 : 1318-1321, 1998

15 Biggs WH 3rd, "Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1" 96 : 7421-7426, 1999

16 Sarbassov DD, "Phosphorylation and regulation of Akt/PKB by the rictormTOR complex" 307 : 1098-1101, 2005

17 Bozulic L, "PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival" 30 : 203-213, 2008

18 Ahn JY, "PIKE/nuclear PI 3-kinase signaling mediates the antiapoptotic actions of NGF in the nucleus" 23 : 3995-4006, 2004

19 Il-Sun Kwon, "PI(3,4,5)P3 regulates the interaction between Akt and B23 in the nucleus" 생화학분자생물학회 43 (43): 127-132, 2010

20 Ahn JY, "Nucleophosmin/B23, a nuclear PI(3,4,5)P(3) receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD" 18 : 435-445, 2005

21 Okuda M, "Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication" 103 : 127-140, 2000

22 Neri LM, "Nuclear trans location of phosphatidylinositol 3-kinase in rat pheochromocytoma PC 12 cells after treatment with nerve growth factor" 40 : 619-626, 1994

23 Lee SB, "Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival" 105 : 16584-16589, 2008

24 Ahn JY, "Nuclear Akt associates with PKC-phosphorylated Ebp1, preventing DNA fragmentation by inhibition of caspase-activated DNase" 25 : 2083-2095, 2006

25 Jones PF, "Molecular cloning of a second form of rac protein kinase" 2 : 1001-1009, 1991

26 Meier R, "Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta" 272 : 30491-30497, 1997

27 Hingorani K, "Mapping the functional domains of nucleolar protein B23" 275 : 24451-24457, 2000

28 Choi JW, "Lysine 263 residue of NPM/B23 is essential for regulating ATP binding and B23 stability" 582 : 1073-1080, 2008

29 Hegde V, "Knockdown of ribosomal protein S3 protects human cells from genotoxic stress" 6 : 94-99, 2007

30 del Peso L, "Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt" 278 : 687-689, 1997

31 Yoo JY, "Interaction of the PA2G4(EBP1)protein with ErbB-3 and regulation of this binding by heregulin" 82 : 683-690, 2000

32 Konishi H, "Identification of peripherin as a Akt substrate in neurons" 282 : 23491-23499, 2007

33 Feng J, "Identification of a PKB/Akt hydrophobic motif Ser-473kinase as DNA-dependent protein kinase" 279 : 41189-41196, 2004

34 Hervy M, "From the membrane to the nucleus and back again : bifunctional focal adhesion proteins" 18 : 524-532, 2006

35 Kops GJ, "Forkhead transcription factors : new insights into protein kinase B(c-akt)signaling" 77 : 656-665, 1999

36 Liu Z, "Ebp1 isoforms distinctively regulate cell survival and differentiation" 103 : 10917-10922, 2006

37 Vogel KS, "Development of trophic interactions in the vertebrate peripheral nervous system" 7 : 363-382, 1993

38 Koh H, "Cloning and characterization of a nuclear S6kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt" 18 : 5115-5119, 1999

39 Du K, "Characterization of a CREB gain-of-function mutant with constitutive transcriptional activity in vivo" 20 : 4320-4327, 2000

40 Kato T, "Atrial natriuretic peptide promotes cardiomyocyte survival by cGMPdependent nuclear accumulation of zyxin and Akt" 115 : 2716-2730, 2005

41 Naora H, "Altered cellular responses by varying expression of a ribosomal protein gene : sequential coordination of enhancement and suppression of ribosomal protein S3a gene expression induces apoptosis" 141 : 741-753, 1998

42 Brunet A, "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor" 96 : 857-868, 1999

43 Chan CB, "Akt phosphorylation of zyxin mediates its interaction with acinus-S and prevents acinus-triggered chromatin condensation" 14 : 1688-1699, 2007

44 Datta SR, "Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery" 91 : 231-241, 1997

45 Xuan Nguyen TL, "Akt phosphorylation is essential for nuclear translocation and retention in NGF-stimulated PC12 cells" 349 : 789-798, 2006

46 Hu Y, "Akt phosphorylates acinus and inhibits its proteolytic cleavage, preventing chromatin condensation" 24 : 3543-3554, 2005

47 Masuyama N, "Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis" 276 : 32799-32805, 2001

48 Yamaguchi A, "Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53" 276 : 5256-5264, 2001

49 Sahara S, "Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation" 401 : 168-173, 1999

50 Cheng JQ, "AKT2, a putative oncogene encoding a member of a subfamily of proteinserine/threonine kinases, is amplified in human ovarian carcinomas" 89 : 9267-9271, 1992

51 Brodbeck D, "A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain" 274 : 9133-9136, 1999