An Analog of a Dipeptide-like Structure of FK506 Increases Glial Cell Line-derived Neurotrophic Factor Expression Through CAMP Response Element-binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

Overview

Journal J Neurosci

Specialty Neurology

Date 2006 Mar 24

PMID 16554484

Citations 14

Authors

Xiaobo Cen

Atsumi Nitta

Shin Ohya

Yinglan Zhao

Naoya Ozawa

Akihiro Mouri

Daisuke Ibi

Li Wang

Makiko Suzuki

Kuniaki Saito

Yasutomo Ito

Tetsuya Kawagoe

Yukihiro Noda

Yoshihisa Ito

Shoei Furukawa

Toshitaka Nabeshima

Affiliations

Soon will be listed here.

Abstract

Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic factor that has therapeutic implications for neurodegenerative disorders. We previously showed that leucine-isoleucine (Leu-Ile), an analog of a dipeptide-like structure of FK506 (tacrolimus), induces GDNF expression both in vivo and in vitro. In this investigation, we sought to clarify the cellular mechanisms underlying the GDNF-inducing effect of this dipeptide. Leu-Ile transport was investigated using fluorescein isothiocyanate-Leu-Ile in cultured neurons, and the results showed the transmembrane mobility of this dipeptide. By liquid chromatography-mass spectrometry and quartz crystal microbalance assay, we identified heat shock cognate protein 70 as a protein binding specifically to Leu-Ile, and molecular modeling showed that the ATPase domain is the predicted binding site. Leu-Ile stimulated Akt phosphorylation, which was attenuated significantly by heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA). Moreover, enhanced interaction between phosphorylated Akt and Hsp90 was detected by immunoprecipitation. Leu-Ile elicited an increase in cAMP response element binding protein (CREB) phosphorylation, which was inhibited by GA, indicating that CREB is a downstream target of Hsp90/Akt signaling. Leu-Ile elevated the levels of GDNF mRNA and protein expression, whereas inhibition of CREB blocked such effects. Leu-Ile promoted the binding activity of phosphorylated CREB with cAMP response element. These findings show that CREB plays a key role in transcriptional regulation of GDNF expression induced by Leu-Ile. In conclusion, Leu-Ile activates Hsp90/Akt/CREB signaling, which contributes to the upregulation of GDNF expression. It may represent a novel lead compound for the treatment of dopaminergic neurons or motoneuron diseases.

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References

Young D, Lawlor P, Leone P, Dragunow M, During M . Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med. 1999; 5(4):448-53. DOI: 10.1038/7449. View

Gold B, Densmore V, Shou W, Matzuk M, Gordon H . Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506. J Pharmacol Exp Ther. 1999; 289(3):1202-10. View

Roberson E, English J, Adams J, Selcher J, Kondratick C, Sweatt J . The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J Neurosci. 1999; 19(11):4337-48. PMC: 6782591. View

Baecker P, Lee W, Verity A, Eglen R, Johnson R . Characterization of a promoter for the human glial cell line-derived neurotrophic factor gene. Brain Res Mol Brain Res. 1999; 69(2):209-22. DOI: 10.1016/s0169-328x(99)00106-0. View

Morshauser R, Hu W, Wang H, Pang Y, Flynn G, Zuiderweg E . High-resolution solution structure of the 18 kDa substrate-binding domain of the mammalian chaperone protein Hsc70. J Mol Biol. 1999; 289(5):1387-403. DOI: 10.1006/jmbi.1999.2776. View

Konishi H, Fujiyoshi T, Fukui Y, Matsuzaki H, Yamamoto T, Ono Y . Activation of protein kinase B induced by H(2)O(2) and heat shock through distinct mechanisms dependent and independent of phosphatidylinositol 3-kinase. J Biochem. 1999; 126(6):1136-43. DOI: 10.1093/oxfordjournals.jbchem.a022559. View

Johnson J, Chu A, Sato-Bigbee C . Possible role of CREB in the stimulation of oligodendrocyte precursor cell proliferation by neurotrophin-3. J Neurochem. 2000; 74(4):1409-17. DOI: 10.1046/j.1471-4159.2000.0741409.x. View

Pugazhenthi S, Nesterova A, Sable C, Heidenreich K, Boxer L, Heasley L . Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem. 2001; 275(15):10761-6. DOI: 10.1074/jbc.275.15.10761. View

Rajapandi T, Greene L, Eisenberg E . The molecular chaperones Hsp90 and Hsc70 are both necessary and sufficient to activate hormone binding by glucocorticoid receptor. J Biol Chem. 2000; 275(29):22597-604. DOI: 10.1074/jbc.M002035200. View

10.

Sato S, Fujita N, Tsuruo T . Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci U S A. 2000; 97(20):10832-7. PMC: 27109. DOI: 10.1073/pnas.170276797. View

11.

Tanaka M, Ito S, Kiuchi K . Novel alternative promoters of mouse glial cell line-derived neurotrophic factor gene. Biochim Biophys Acta. 2000; 1494(1-2):63-74. DOI: 10.1016/s0167-4781(00)00218-9. View

12.

Nollen E, Kabakov A, Brunsting J, Kanon B, Hohfeld J, Kampinga H . Modulation of in vivo HSP70 chaperone activity by Hip and Bag-1. J Biol Chem. 2000; 276(7):4677-82. DOI: 10.1074/jbc.M009745200. View

13.

Brunet A, Datta S, Greenberg M . Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol. 2001; 11(3):297-305. DOI: 10.1016/s0959-4388(00)00211-7. View

14.

Richter K, Buchner J . Hsp90: chaperoning signal transduction. J Cell Physiol. 2001; 188(3):281-90. DOI: 10.1002/jcp.1131. View

15.

Schinelli S, Zanassi P, Paolillo M, Wang H, Feliciello A, Gallo V . Stimulation of endothelin B receptors in astrocytes induces cAMP response element-binding protein phosphorylation and c-fos expression via multiple mitogen-activated protein kinase signaling pathways. J Neurosci. 2001; 21(22):8842-53. PMC: 6762276. View

16.

McLaughlin S, Smith H, Jackson S . Stimulation of the weak ATPase activity of human hsp90 by a client protein. J Mol Biol. 2002; 315(4):787-98. DOI: 10.1006/jmbi.2001.5245. View

17.

Pearl L, Prodromou C . Structure, function, and mechanism of the Hsp90 molecular chaperone. Adv Protein Chem. 2002; 59:157-86. DOI: 10.1016/s0065-3233(01)59005-1. View

18.

Thulasiraman V, Yun B, Uma S, Gu Y, Scroggins B, Matts R . Differential inhibition of Hsc70 activities by two Hsc70-binding peptides. Biochemistry. 2002; 41(11):3742-53. DOI: 10.1021/bi012137n. View

19.

Airaksinen M, Saarma M . The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci. 2002; 3(5):383-94. DOI: 10.1038/nrn812. View

20.

Rubio E, Valenciano A, Segundo C, Sanchez N, de Pablo F, de la Rosa E . Programmed cell death in the neurulating embryo is prevented by the chaperone heat shock cognate 70. Eur J Neurosci. 2002; 15(10):1646-54. DOI: 10.1046/j.1460-9568.2002.01998.x. View