臺灣博碩士論文加值系統

腺苷酸2A亞型受體(A2A adenosine receptor，簡稱為A2AR)屬於G蛋白聯結型受體，已被發現分布在大腦中的主要區域，並且參與調控神經細胞的生理功能。我們的研究證明A2AR 的C端會藉著結合一個參與DNA修復及訊息RNA運送的蛋白Translin associated protein X (TRAX)，來調控細胞中由神經生長因子所引發的神經軸突生長現象。我們的實驗發現海馬迴神經細胞的神經軸突發生(neuritogenesis)需要p53蛋白的存在，因為抑制了p53蛋白的功能就會抑制神經軸突發生。我們更進一步證實，活化A2AR後可透過TRAX來抑制細胞增生，並修復因p53被抑制而停止的神經軸突發生現象(簡稱為A2A恢復作用)。在目前的研究結果中，會與TRAX發生交互作用的KIF2A蛋白質亦被發現在A2A恢復作用中扮演關鍵的角色。實驗結果發現若降低KIF2A的表現量會抑制A2A恢復作用，若大量表現KIF2A，可以恢復因p53被抑制而停止的神經軸突生長現象。在神經分化細胞模型PC12中，我們發現給予神經生長因子的刺激會讓TRAX及KIF2A在細胞核中共存。因此我們利用KIF2A514片段來破壞TRAX和KIF2A的相互作用，並且發現A2A恢復作用會因此受到抑制。這些實驗結果都證實了TRAX和KIF2A之間的功能性交互作用在A2A恢復作用中扮演具關鍵性的作用。此外，我們的結果也證實了當p53被抑制時，KIF2A無法因為神經生長因子的刺激而從細胞核轉移到細胞質。我們進一步證實會滯留在細胞核的KIF2A-NLS 變異蛋白無法像正常的KIF2A一樣，進行A2A恢復作用。因此，讓KIF2A重新轉移到細胞質是造成神經軸突生長的必要條件。總結我們的實驗結果，我們發現KIF2A參與了海馬迴神經細胞及PC12 細胞的神經軸突發生現象。我們並推論活化A2AR 可以復原由於p53被抑制而受損的神經軸突生長(即A2A恢復作用)可能經由TRAX及KIF2A的功能性交互作用及重新轉移因p53被抑制而滯留細胞核的KIF2A到細胞質去調控神經軸突生長功能。

The A2A adenosine receptor (A2AR) is a G protein-coupled receptor. We previously reported that the C-terminus of the A2AR binds to translin-associated protein X (TRAX) and modulates nerve growth factor (NGF)-evoked neurite outgrowth in PC12 cells. Herein, I show that neuritogenesis of primary hippocampal neurons requires p53 because blockage of p53 suppressed neurite outgrowth. The impaired neuritogenesis caused by p53 blockage was rescued by activation of the A2AR (designated the A2A rescue effect) in a TRAX-dependent manner. Importantly, suppression of a TRAX-interacting protein (kinesin heavy chain member 2A, KIF2A) inhibited the A2A rescue effect, while overexpression of KIF2A caused a rescue effect. Expression of a KIF2A fragment (KIF2A514), which disturbed the interaction between KIF2A and TRAX, blocked the rescue effect. Transient colocalization of TRAX and KIF2A was detected in the nucleus of PC12 cells upon NGF treatment. These data suggest that functional interaction between KIF2A and TRAX is critical for the A2A rescue effect. Moreover, p53 blockage during NGF treatment prevented the redistribution of KIF2A from the nucleus to the cytoplasmic region. Expression of a nuclear-retained KIF2A variant (NLS-KIF2A) did not rescue the impaired neurite outgrowth as did the wildtype KIF2A. Redistribution of KIF2A to the cytoplasmic fraction therefore is a prerequisite for neurite outgrowth. Collectively, we demonstrate that KIF2A functions downstream of p53 to mediate neuritogenesis of primary hippocampal neurons and PC12 cells. Stimulation of the A2AR rescued neuritogenesis impaired by p53 blockage via an interaction between TRAX and KIF2A.

Contents

Contents ………………………………………………………………………….....I
List of Tables …………………………………………………………………...….IV
List of Figures …………………………………………………………… ……… IV
List of Appendix ………………………………………………………………….VII
Abbreviation ……………………………………………………………………..VIII
Abstract (Chinese) ……………………………………………………………….....X
Abstract (English) ………………………………………………………………..XII

Introduction
Tumor suppression gene TP53 ………………………………………………….1
Adenosine 2A receptor (A2AR) ………………………………………………….2
Translin associated protein X (TRAX) ………………………………………….4
Kinesin heavy chain family 2A (KIF2A) ……………………………………….5

Materials and Methods
Reagents ………………………………………………………………………...7
Animals and Cell Culture ……………………………………………………….7
RNA purification and quantitative polymerase chain reaction (QPCR) ………..8
Transfection and neuronal differentiation ………………………………………9
Lentivirus preparation …………………………………………………………11
Western blot analysis …………………………………………………………..11
Immunocytochemistry …………………………………………………………12
BrdU incorporation assay ……………………………………………………...13
[3H]-thymidine incorporation assay …………………………………………...13
Flow Cytometry and Cell Sorting ……………………………………………..14
cAMP Assay …………………………………………………………………...15
Statistical analysis ……………………………………………………………..15

Results
1. Activation of adenosine 2A receptor (A2AR) rescues the impaired neurite outgrowth caused by p53 blockage ………………………………………… ..16
2. A2A rescue effect signals through its C-terminus and the G-ptotein independent pathway ………………………………………………………….17
2.1 PKA and PKC was not involved in the A2A rescue effect …………………...17
2.2 The A2A rescue effect functions via its C-terminus domain …………………18
3. The novel interacting protein, Translin associated protein X(TRAX), mediated the A2A rescue effect in PC12 cell and primary hippocampal neurons …………………………………………………………………………19
3.1 Characterization of the interaction between A2AR and TRAX ………………19
3.2 Overexpression of TRAX rescued the impaired neurite outgrowth and suppression of TRAX diminished the rescue effect ……………………………...21
3.3 TRAX suppressed the proliferation of PC12 cell and promotes the neurite outgrowth impaired by p53 blockage …………………………………………...22
4. The molecular mechanism of the TRAX signalosome in the A2A rescue effect
4.1 The TRAX interacting protein, KIF2A, is involved in the A2A rescue effect….23
4.2 Functional interaction of TRAX and KIF2A in the nucleus is critical for A2A rescue effect …………………………………………………………………24
4.3Cytosolic accumulation of KIF2A and nuclear enrichment of TRAX are prerequisites for the A2A rescue effect ………………………………………26
Discussion ………………………………………………………………………...28
Conclusion and Perspectives ………………………………………………...38
References ………………………………………………………………………..40
Tables ……………………………………………………………………………..56
Figures …………………………………………………………………………….62
Appediex ………………………………………………………………………….95




List of Tables

Table 1. PKA was not required for the rescue effect of A2AR ……………………..57
Table 2. PKC was not required for the rescue effect of A2AR ……………………..58
Table 3. Stimulation of A2AR Blocked BrdU incorporation through its interacting protein, TRAX ……………………………………………………………59
Table 4. Sequences of primers used in the construction of KIF2A and TRAX variant …………………………………………………………………….60
Table 5. Small hairpin (sh)RNA sequences used in the present study …………….61

List of Figures

Fig.1 Primary hippocampal neurons harvested from p53-null mice had shorter neuronal process. …………………………………………………………63
Fig.2 Stimulation of the A2A adenosine receptor (A2AR) rescues impaired
neurite development caused by p53 blockage in primary hippocampal neurons. …………………………………………………………………..64
Fig.3 Protein kinase A (PKA) was not involved in the A2A adenosine receptor (A2AR) rescue effect on primary hippocampal neurons. …………………66
Fig.4 The C-terminus of the A2A adenosine receptor (A2AR) mediated the A2A rescue effect in primary hippocampal neurons. …………………………..67
Fig.5 The A2AR interacted with TRAX at its C terminal domain. ……………...69
Fig.6 Colocalization of the A2AR and TRAX in vivo. ………………………….70
Fig.7 An A2A adenosine receptor (A2AR)-binding protein, TRAX, is required for the A2A rescue effect in primary neurons. ………………………………..71
Fig.8 A2AR stimulation restored NGF’s ability to suppress proliferation in the presence of R273H-p53 ([3H]thymidine incorporation assay). ……………72
Fig.9 KIF2A rescued the nerve growth factor (NGF)-induced neurite outgrowth impaired by p53 blockage without affecting the proliferation of PC12
cells. ………………………………………………………………………73
Fig.10 An interacting protein of TRAX, KIF2A, mediated the adenosine 2A (A2A) rescue effect. ……………………………………………………………...75
Fig.11 The PC12 cell line permanently expressing a p53 dominant negative mutant (R273H-PC12) lost its ability to produce neurite outgrowth upon nerve growth factor (NGF) treatment. ………………………………………….78
Fig.12 Downregulation of p53 by small hairpin (sh)RNAs. …………………….79
Fig.13 A TRAX interacting protein kinesin heave chain family 2, KIF2A, is required for the A2A rescue effect in primary neurons. …………………..80
Fig.14 Functional interaction between TRAX and KIF2A was required for the rescue effect. ……………………………………………………………..81
Fig.15 Redistribution of KIF2A into the cytoplasmic region of PC12 cells was a prerequisite for nerve growth factor (NGF)-induced neurite outgrowth.…84
Fig.16 Cellular localizations of NLS-KIF2A and DNLS-TRAX in PC12 cells.….88
Fig.17 KIF2A was retained in nuclei of a PC12 cell line permanently expressing p53-R273H (designated PC12-R273H). …………………………………90
Fig.18 Functional interaction between TRAX and KIF2A is required for the A2A adenosine receptor (A2AR)-regulated cellular distribution of KIF2A.……91
Fig.19 Activation of the A2A adenosine receptor (A2AR) normalized the abnormal distribution of TRAX caused by p53 blockage during nerve growth factor (NGF) treatment in PC12 cells. ………………………………………….93





List of Appendix
Fig.20 An inhibitor of p53 (PFT-a) prevented the localization of KIF2A at the tips of growing neuronal processes in primary hippocampal neurons. ……….96
Fig.21 TRAXK279R mutant attenuated the rescue effect. …………………………97
Fig.22 The working model of TRAX- and KIF2A-mediated A2AR rescue effect. ……………………………………………………………………..98

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