臺灣博碩士論文加值系統

長期記憶的形成，已知CREB磷酸化和訊息傳遞扮演重要角色，然而目前對於CREB其他轉譯後修飾知道的並不多。此研究我們發現，CREB短片段異型體1Δ的賴氨酸殘基位置271和290會被類泛素E3連接酶 (E3 ligase) PIAS1類泛素化，並且當PIAS1類泛素化CREB1Δ後會增加CREB1Δ的表現量。此研究也發現CREB1Δ會被其他的PIAS家族類泛素化，但卻不會被其他的E3連接酶RanBP2和Pc2以及單獨的E2連接酶 (E2 ligase) UBC9類泛素化。此外，經過水迷津訓練的大白鼠其海馬迴CA1區域中的CREB會被類泛素化，然而其他腦區的CREB並沒有發現這種現象。另外，我們轉導慢病毒CREB到大白鼠CA1腦區中發現，野生型CREB會促進大白鼠的空間學習與記憶，然而轉導類泛素化雙重突變型的CREB (CREBK271RK290R) 到大白鼠的CA1腦區則會降低大白鼠的空間學習與記憶。然而轉導慢病毒CREB-SUMO1融合蛋白到大白鼠的CA1腦區則會促進大白鼠的空間學習與記憶以及CREB的類泛素化。我們也發現轉導野生型慢病毒CREB會增加，而轉導類泛素化雙重突變型的CREB會降低，CREB結合到腦源神經滋養因子 (brain-derived neurotrophic factor, BDNF) 的啟動子以及影響其mRNA的表現。利用小干擾RNA減弱大白鼠腦中CA1區域的PIAS1後發現，減弱PIAS1會降低大白鼠的空間學習與記憶並會減少內生性CREB的類泛素化。另外，我們發現CREB的類泛素化是依賴CREB的磷酸化，並且類泛素化的CREB可以維持得較久。由此推測，在長期記憶過程中CREB的磷酸化是反映長期記憶形成初期的訊號傳遞，而CREB的類泛素化則可使長期記憶維持較長的時間。

cAMP-responsive element binding protein (CREB) phosphorylation and signaling plays an important role in long-term memory formation, but other posttranslational modifications of CREB are less known. Here, we found that CREB1Δ, the short isoform of CREB, could be sumoylated by the small ubiquitin-like modifier (SUMO) E3 ligase protein inhibitor of activated STAT1 (PIAS1) at Lys271 and Lys290 and PIAS1 SUMOylation of CREB1Δ increased the expression level of CREB1Δ. CREB1Δ could also be sumoylated by other PIAS family proteins, but not by the E3 ligases RanBP2 and Pc2 or by the E2 ligase Ubc9. Furthermore, water maze training increased the level of endogenous CREB SUMOylation in rat CA1 neurons determined by in vitro SUMOylation assay, but this effect was not observed in other brain areas. Moreover, transduction of Lenti-CREBWT to rat CA1 area facilitated, whereas transduction of Lenti-CREB double sumo-mutant (CREBK271RK290R) impaired, spatial learning and memory performance. Transduction of Lenti-CREBWT-SUMO1 fusion vector to rat CA1 area showed a more significant effect in enhancing spatial learning and memory and CREB SUMOylation. Lenti-CREBWT transduction increased, whereas Lenti-CREBK271RK290R transduction decreased, CREB DNA binding to the brain-derived neurotrophic factor (bdnf) promoter and decreased bdnf mRNA expression. Knock-down of PIAS1 expression in CA1 area by PIAS1 siRNA transfection impaired spatial learning and memory and decreased endogenous CREB SUMOylation. In addition, CREB SUMOylation was CREB phosphorylation dependent and lasted longer. Therefore, CREB phosphorylation may be responsible for signal transduction during the early phase of long-term memory formation, whereas CREB SUMOylation sustains long-term memory.

Table of Contents

Table of Contents I
List of Figures IV
Abbreviations VI
中文摘要 VIII
Abstract IX
Chapter 1. Introduction 1
1-1. Learning and memory 1
1-2. Types of memory 2
1-3. Localization involves memory 3
1-4. Anatomy of the hippocampal network 4
1-5. Hippocampal connectivity 6
1-6. Functions of the dorsal and ventral hippocampus 8
1-7. Functional roles of EC, DG, CA3, and CA1 10
1-8. CREB 12
1-8-1. CREB structure and regulation 14
1-8-2. Additional CREB PTM 15
1-8-3. CREB and memory 16
1-8-4. CREB and spatial memory 17
1-9. PIAS1 18
1-10. The process of SUMOylation 20
Specific Aims 22
Chapter 2: Materials and Methods 23
2-1. Animals 23
2-2. Drugs 23
2-3. Plasmid DNA construction 23
2-4. His-PIAS1 and His-CREB fusion protein purification 26
2-5. In vitro SUMOylation assay 27
2-6. Plasmid transfection to HEK293T cells 28
2-7. Lentivirus preparation 28
2-8. Intra-hippocampal lentiviral vector transduction 29
2-9. Intra-hippocampal plasmid DNA transfection and siRNA interference 29
2-10. Western blot 31
2-11. Immunoprecipitation (IP) and co-IP 31
2-12. IP and in vitro SUMOylation assay in CA1 tissue 32
2-13. Biotinylated oligonucleotides pull-down assay for CREB DNA-bindin 33
2-14. Chromatin immunoprecipitation (ChIP) assay 34
2-15. ChIP quantitative real-time PCR 34
2-16. Quantitative real-time PCR 35
2-17. Immunohistochemistry 35
2-18. Water maze learning 36
2-19. Statistics 37
Chapter 3. Results 38
3-1. CREB is sumoylated by SUMOylation machinery and PIAS1 in vitro 38
3-2. CREB is sumoylated by PIAS1 and associated with PIAS1 in HEK293T
cells 39
3-3. Identification of the major SUMO sites on CREB 39
3-4. CREB is sumoylated by all of the PIAS family members in HEK293T
cells 41
3-5. PIAS1 SUMOylation of CREB increases the expression level of CREB 41
3-6. CREB is sumoylated by PIAS1 in the nucleus of hippocampus 42
3-7. CREB double sumo-mutant impairs CREB SUMOylation in CA1 42
3-8. NMDA injection increases PIAS1 activity and CREB SUMOylation 43
3-9. Time course change of CREB phosphorylation and CREB SUMOylation
after spatial training 44
3-10. CREB double sumo-mutant impairs spatial learning and memory 45
3-11. CREB double sumo-mutant impairs bdnf promoter binding and bdnf
mRNA expression 46
3-12. Transduction CREB-SUMO1 fusion vector enhances spatial learning
and memory and increases CREB SUMOylation 47
3-13. PIAS1 siRNA transfection impairs spatial learning and memory and
decreases CREB SUMOylation 48
3-14. CREB SUMOylation is CREB phosphorylation dependent 48
Chapter 4 Discussion 51
4-1. CREB is sumoylated by SUMOylation machinery in vitro and requires
the E3 ligase PIAS1 in HEK293T cells 51
4-2. CREB is sumoylated by PIAS family proteins, and CREB SUMOylation
enhances CREB protein level in HEK293T cells 52
4-3. Spatial training increases endogenous CREB SUMOylation in rat CA1
area 53
4-4. CREB double sumo-mutant decreases bdnf promoter binding as well
as mRNA expression, and CREB-SUMO1 fusion protein increases
spatial learning and memory 54
4-5. PIAS1 regulates CREB SUMOylation in the CA1 area 54
Conclusion 57
References 58

List of Figures

Figure 1. Alignment and comparison of CREB1 and CREB1Δ isoforms 75
Figure 2. CREB is sumoylated by PIAS1 in vitro 76
Figure 3. CREB has a shifted band under PIAS1 cotransfection in HEK293T
cells 77
Figure 4. Determining that the shifted band is sumoylated CREB in HEK293T
cells 78
Figure 5. PIAS1 is associated with CREB in HEK293T cells 79
Figure 6. Identification of the major SUMOylation sites on CREB 81
Figure 7. Double mutations on CREB at Lys271 and Lys290 dramatically
decreases CREB SUMOylation in HEK293T cells 82
Figure 8. CREB SUMOylation by PIAS family but not the E2 ligase only or
other E3 ligases 83
Figure 9. Overexpression PIAS1 increases the expression level of CREB in
HEK293T cells 84
Figure 10. PIAS1 interacts with CREB and most of sumoylated CREB is in the
nucleus in rat hippocampus 85
Figure 11. Identification of CREB SUMOylation sites in rat hippocampus 86
Figure 12. NMDA enhances E3 ligase activity of PIAS1 and disrupts by the
ligase-deficient mutant 87
Figure 13. Confirmation of intra-hippocampal transfection 88
Figure 14. CREB phosphorylation and SUMOylation after 1 day spatial training
in rat CA1 area 89
Figure 15. CREB phosphorylation and SUMOylation after 2 days spatial training
in rat CA1 area 90
Figure 16. CREB phosphorylation and SUMOylation after 5 days spatial training
in rat CA1 area 91
Figure 17. CREB phosphorylation and SUMOylation after 5 days spatial training
in rat striatum and amygdala 92
Figure 18. CREB double sumo-mutant impairs spatial learning and memory 93
Figure 19. CREB double sumo-mutant decreases CREB SUMOylation and
DNA binding 94
Figure 20. CREB double sumo-mutant does not alter visible platform learning 95
Figure 21. CREB double sumo-mutant decreases bdnf promoter binding and
bdnf mRNA expression 96
Figure 22. Transduction of Lenti-CREB-SUMO1 to rat CA1 area enhances
spatial learning and memory 97
Figure 23. Transduction of Lenti-CREB-SUMO1 to rat CA1 area increases
CREB SUMOylation 98
Figure 24. Knockdown of PIAS1 impairs spatial learning and memory 99
Figure 25. Knockdown of PIAS1 decreases CREB SUMOylation 100
Figure 26. CREB SUMOylation is CREB phosphorylation dependent 101
Figure 27. CREB double sumo-mutant does not affect CREB phosphorylation 102
Figure 28. Schematic diagram showing the relationships among spatial training,
PIAS1 expression, CREB SUMOylation, BDNF expression, and
spatial memory formation 103

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