MST1促进细胞凋亡机制方面的研究

发布时间：2018-02-04 01:37

  本文关键词： 细胞凋亡 p53 丝氨酸苏氨酸蛋白激酶 信号转导 SIRT　出处：《第三军医大学》2010年博士论文　论文类型：学位论文

【摘要】：背景与目的 蛋白激酶MST1(mammalian Sterile 20-like kinase 1)在其氨基端有一个Ste20相关的激酶催化域,羧基端有一个调节区。MST1在细胞增殖、分化、形态和细胞骨架重排方面发挥了重要作用。先前已有研究指出氨基端催化域的缺失会使MST1被半胱氨酸蛋白酶3(caspase-3)在为数众多的细胞凋亡刺激素的作用下所切割,例如由CD95/FasL触发的死亡受体,或被星孢菌素(STS),神经酰胺,热休克和亚砷酸盐处理。被切割后的MST1的氨基末端会转移至核内,然后对于染色质的固缩和随后发生的细胞凋亡产生一定的作用。而且,有实验表明在细胞内过表达MST1的情况下,已经发现了其被切割的情况和因此诱发的细胞凋亡。并且已经有报道证实第326和第349位的天冬氨酸是两个主要的切割位点。突变掉这些切割位点后,MST1的激活,核转位和诱导细胞凋亡的能力都会明显减弱。最近已经明确了在MST1的第八亚结构域的第183位的苏氨酸是其主要的磷酸激活位点并且这个苏氨酸位点的自磷酸化对于MST1激酶的激活是必须的。Hippo是哺乳动物的MST1在果蝇中的同源蛋白,并且已经被大量实验证实其通过抑制转录和(或者)降解细胞周期蛋白E(cyclin E)和DIAPs或者磷酸化并抑制Yorkie来限制细胞生长和增殖。在哺乳动物中,MST1已经被证实可以分别通过促细胞分裂剂激活性蛋白激酶激酶4/促细胞分裂剂激活性蛋白激酶激酶7(MKK4/MKK7)和促细胞分裂剂激活性蛋白激酶激酶3/促细胞分裂剂激活性蛋白激酶激酶6(MKK3/MKK6)激活c-Jun氨基末端激酶(JNK)和p38MAPK激酶信号通路。最近有报道称JNK对于MST1的激活和由MST1介导的通过磷酸化MST1上的第82位丝氨酸引起的细胞凋亡是必须的。此外,JNK的显性失活突变体能抑制MST1诱导的caspase的激活和从而产生的细胞凋亡,而p38的显性失活突变体和p38抑制剂则不能抑制MST1诱导的细胞凋亡。 MST1还能通过磷酸化组蛋白H2B上相对保守的位点(哺乳动物细胞上第14位丝氨酸,酵母菌上第10位丝氨酸)来诱导的细胞凋亡。我们实验室的研究表明MST1能通过磷酸化O亚型叉头框3a(FOXO3a)上的第207位丝氨酸和FOXO1上对应的第212位丝氨酸从而涉及依赖于FOXO的神经元细胞凋亡过程。近期我们还发现磷酸肌醇3(phosphoinositide 3)激酶/Akt能磷酸化第120位苏氨酸从而抑制MST1介导的细胞凋亡前信号通路。 沉默信息调节因子2相关酶1(Sirt1)是NAD+依赖的去乙酰化酶,它有相当数量的底物并且参与了多种细胞进程。去乙酰化这些靶蛋白导致其蛋白活性既有可能被抑制也有可能被激活,从而影响机体生理的许多方面,例如转录沉默,基因水平控制的寿命长短,细胞的新陈代谢,能量的动态平衡,DNA修复和细胞存活。P53作为一个关键肿瘤抑制基因,在反馈细胞所接受的众多压力信号包括DNA损伤,组织缺氧和异常增殖过程中发挥了极其重要的作用。P53维持基因组稳定性的方式主要是依赖于p53诱导的细胞凋亡,包括抑制肿瘤生长或是清除肿瘤。总的来说,p53应对DNA损伤的生物活性是和其转录后的修饰状态密切相关的,特别是特殊位点的磷酸化、乙酰化和泛素化。Sirt1已经被报道能强烈与其底物p53结合,并能去乙酰化p53的第382位赖氨酸。Sirt1介导的去乙酰化能对抗依赖于p53的转录激活并能特定地抑制在DNA损伤或氧化应激下引起的依赖于p53的细胞凋亡。 先前的研究已经指出MST1促进的细胞凋亡有可能是依赖于p53的,但是MST1-p53在细胞凋亡过程中信号通路的分子机制还有很大一部分都是未知。所以本研究旨在明确MST1在遗传毒性因子诱导的依赖于p53的细胞凋亡过程中扮演的角色,并期待着能发现MST1、Sirt1和p53在这个过程中的相互调节机制。 方法 1.1 MST1和Sirt1对p53和p21转录活性的影响 A. H1299细胞在转染14*p53人工荧光素酶报告基因的同时分别共转了p53、MST1、MST1 K59R和Sirt1质粒。细胞裂解液用双荧光素酶报告基因系统检测转录活性。B. H1299细胞在转染p21启动子荧光素酶报告基因的同时分别共转了p53、MST1和Sirt1质粒。细胞裂解液用双荧光素酶报告基因系统检测转录活性。 1.2 MST1和Sirt1对p53介导的细胞凋亡的影响 A. U2OS细胞转染编码MST1和p53 shRNA或者空载体的质粒,然后用Etoposide处理36小时后用流式细胞仪检测Annexin-V染色的细胞凋亡情况。B. HCT116 p53+/+和HCT116 p53-/-细胞被稳定转染MST1,对照组稳定转染空载体,然后用CDDP处理36小时后用流式细胞仪检测Annexin-V染色的细胞凋亡情况。C. HCT116 p53+/+和HCT116 p53-/-细胞转染MST1的小干扰RNA,对照组转染随机小干扰RNA,然后用CDDP处理48小时后用流式细胞仪检测Annexin-V染色的细胞凋亡情况。D. U2OS细胞在转染MST1质粒的同时共转Sirt1质粒或空载体。用Etoposide处理36小时后用流式细胞仪检测Annexin-V染色的细胞凋亡情况。 2.1 MST1对Sirt1介导的p53去乙酰化作用的影响 A.稳定转染MST1的HCT116 p53+/+细胞和其稳定转染空载体的对照组细胞的裂解液用免疫印迹方法检测,所用的抗体包括抗p53-k382乙酰化抗体和抗p53抗体。上样量通过内参14-3-3β蛋白调整,从而保持一致。B.转染HA-p53或同时转染GFP-MST1的细胞中FLAG-Sirt1的免疫沉淀物用免疫印迹方法检测,所用的抗体包括抗HA抗体和抗FLAG抗体。C.转染p53、p300、Sirt1、MST1质粒的293T细胞的裂解液用免疫印迹方法检测,所用抗体有抗p53-k382乙酰化抗体等。 2.2 MST1如何通过和Sirt1作用增强p53乙酰化 A.体外MST1激酶实验,重组MST1蛋白和其底物GST-Sirt1在32P-ATP存在的情况下进行孵育。反应后用聚丙烯酰胺凝胶电泳分离蛋白质进行荧光放射自显影术测定。B.体外MST1激酶实验,有活性的重组MST1蛋白在32P-ATP存在的情况下和不同的Sirt1蛋白片段(P1、P2、P3)进行孵育。反应后用聚丙烯酰胺凝胶电泳分离蛋白质进行荧光放射自显影术测定。C.体外磷酸化实验,有活性的MST1蛋白和Sirt1蛋白在不带放射性的ATP存在的情况下进行孵育,然后将磷酸化实验产物和乙酰化p53孵育进行去乙酰化实验。反应后用聚丙烯酰胺凝胶电泳分离蛋白质并用免疫印迹方法检测,所用抗体有抗p53-K382乙酰化抗体、抗GST抗体和抗Sirt1抗体。 结果与结论 1.1 MST1通过抑制Sirt1活性增强p53转录活性。 在14*p53报告基因中,Sirt1能显著抑制p53的表达,而野生型MST1能明显挽救Sirt1诱导的p53降低,但是ATP结合位点突变的激酶活性失活的MST1(MST1 K59R)不能挽救Sirt1诱导的p53降低。与之相似的,Sirt1抑制了依赖于p53的p21荧光素酶活性,而MST1可以逆转Sirt1诱导的p21表达的降低。综上所述,MST1通过抑制Sirt1来促进p53的转录活性。 1.2 MST1促进细胞凋亡是依赖于p53并且Sirt1能抑制MST1诱导的细胞凋亡。 U2OS细胞在干扰掉p53基因的情况下过表达MST1,用Etoposide处理后,细胞凋亡减少。我们在HCT116 p53-/-细胞中也发现MST1的稳定表达不能增加Cisplatin诱导的细胞凋亡数目,但是在HCT116 p53+/+细胞中MST1的稳定表达却能增加Cisplatin诱导的细胞凋亡数目,并且我们还发现在HCT116 p53+/+细胞中干扰掉MST1后Cisplatin诱导的细胞凋亡明显减少而在HCT116 p53-/-细胞中干扰掉MST1后Cisplatin诱导的细胞凋亡不能被降低。这些实验证据证明MST1在DNA损伤情况下促进细胞凋亡是依赖于p53。同时在Sirt1过表达细胞中,MST1介导的细胞凋亡会减少。 2.1 MST1抑制Sirt1介导的p53去乙酰化。 我们在体外MST1激酶实验中发现MST1不能直接磷酸化p53。而Western blot使用p53特异的乙酰化抗体检测结果表明在MST1过表达细胞中内源p53乙酰化水平有所增高。然后我们用IP实验证明MST1和Sirt1有直接的相互作用。接着,我们观察到MST1的过表达会减弱p53和Sirt1的相互作用。与之一致的,在MST1过表达的细胞中Sirt1介导的p53去乙酰化是被抑制的。综上所述,MST1抑制了Sirt1介导的p53去乙酰化。我们同时发现在体外MST1也能减少Sirt1介导的FOXO3去乙酰化,表明MST1也可能调控Sirt1其他底物的生物活性。 2.2 MST1通过磷酸化Sirt1增加p53乙酰化。 体外MST1激酶实验中用重组Sirt1蛋白作为底物表明Sirt1能被MST1磷酸化。我们接着用重组GST融合蛋白分别编码了3个不重叠的Sirt1区域(肽段P1-P3)并以此指出在Sirt1上的磷酸化区域。在体外激酶实验中显示包含了C末端的第489-747位氨基酸片段的P3是磷酸化的主要区域。在体外磷酸化和去乙酰化实验中,MST1磷酸化Sirt1确实减少了Sirt1诱导的p53去乙酰化。通过以上实验我们阐明了MST1通过负调控Sirt1的去乙酰化活性来调节p53功能的分子机制。
[Abstract]:Background and purpose
Protein kinase MST1 (mammalian Sterile 20-like kinase 1) is a Ste20 kinase catalytic domain related in its N-terminal, C-terminal region of.MST1 has a regulation in cell proliferation, differentiation, play an important role in the morphology and cytoskeleton rearrangement. Previous studies have indicated that deletion of amino terminal catalytic domain of MST1 is cysteine proteinase 3 (caspase-3) by cutting in the numbers of apoptotic stimuli under the action, such as the death receptor triggered by CD95/FasL, or staurosporine (STS), ceramide, heat shock and arsenite treatment. N-tail cleavage of MST1 will transfer to the nucleus, cell then the apoptotic chromatin condensation and subsequent acts. Moreover, experiments have shown that in cells overexpressing MST1, has discovered the cleavage and therefore the cell apoptosis induced by and. And it has been reported that 326th and 349th of the aspartic acid is two major cleavage sites. These mutations fall cleavage sites, MST1 activation, nuclear translocation and apoptosis induction ability will be significantly weakened. Recently it has been defined in the MST1 of the eighth sub domains of 183rd threonine is the main the phosphoric acid activation site and the threonine sites auto phosphorylation of MST1 kinase is required for.Hippo is the mammalian MST1 in Drosophila homologous protein, has been extensively shown through the inhibition of transcription and (or) degradation of cyclin E (cyclin E) and DIAPs or phosphorylation and inhibition of Yorkie the inhibition of cell growth and proliferation. In mammals, MST1 has been proved respectively by the mitogen activated protein kinase kinase 4/ mitogen activated protein kinase kinase 7 (MKK4/MKK7) and mitogen activated protein kinase kinase 3/ mitogen activated protein kinase kinase 6 (MKK3/MKK6) activation of c-Jun N-terminal kinase (JNK) and p38MAPK kinase signal pathway. Recently it has been reported that JNK for MST1 activation and MST1 mediated by phosphorylation on MST1 eighty-second serine induced cell apoptosis is necessary. In addition, the dominant negative mutant of JNK activation can inhibit MST1 induced caspase and resulting in apoptosis, and the dominant negative mutant of p38 and p38 inhibitors can inhibit the cell apoptosis induced by MST1.
Can MST1 through phosphorylation of histone H2B on a relatively conserved sites (mammalian cells on serine fourteenth, yeast serine tenth) induces apoptosis. Our experiments show that MST1 can phosphorylate O subtype of forkhead box 3A (FOXO3a) corresponding to the 207th serine and FOXO1 212nd serine processes involved in neuronal apoptosis and FOXO dependent. Recently we have shown that phosphatidylinositol 3 kinase (phosphoinositide 3) /Akt apoptosis phosphorylation of threonine 120th inhibits MST1 mediated signal pathway.
Silent information regulator 2 (Sirt1) is the 1 enzyme NAD+ - dependent deacetylase, it has a considerable number of substrates and involved in various cellular processes. The deacetylation of these target proteins leads to its protein activity can be suppressed may also be activated, thus affecting many aspects of the physical body, for example transcriptional silencing, genetic control of aging cells, the dynamic balance of energy, The new supersedes the old., DNA repair and cell survival of.P53 as a key tumor suppressor gene, numerous stress signals received in the cellular response including DNA damage, hypoxia and abnormal proliferation of.P53 played a role in the maintenance of genome stability is extremely important the main way is dependent on the cell apoptosis induced by p53, including the inhibition of tumor growth or tumor eradication. In general, the biological activity of p53 in response to DNA damage and its repair after. A closely related state, especially the specific phosphorylation, acetylation and ubiquitination of.Sirt1 has been reported to strongly with the substrate binding to p53, and can deacetylate p53 382nd lysine.Sirt1 mediateddeacetylation antagonizes p53 dependent transcriptional activation and specific inhibition of apoptosis in response to DNA damage or oxidative stress dependent on p53.
Previous studies have shown that MST1 promotes cell death may be dependent on p53, but the molecular mechanism of MST1-p53 signaling pathway in apoptosis is still largely unknown. So the purpose of this study was to play MST1 in the process of apoptosis induced by specific genetic toxicity factor depends on the role of p53, and look forward to to find MST1, Sirt1 and p53 in the process of mutual adjustment mechanism.
Method
The effect of 1.1 MST1 and Sirt1 on the transcriptional activity of p53 and p21
At the same time, A. in H1299 cells transfected with 14*p53 luciferase reporter gene were constructed to p53, MST1, MST1 K59R and Sirt1 plasmid. Cell lysate with dual luciferase reporter system detection of.B. transcriptional activity and H1299 cell activation in transfected p21 promoter luciferase reporter gene respectively with the turn of p53, MST1 and Sirt1 activity of plasmid. The dual luciferase in cell lysates.
The effect of 1.2 MST1 and Sirt1 on p53 mediated apoptosis
A. U2OS and p53 shRNA cells transfected with MST1 encoding plasmid or empty vector, and then use the Etoposide after 36 hours of treatment were detected by flow cytometry with Annexin-V staining the apoptosis of.B. HCT116 p53+/+ and HCT116 p53-/- cells were transfected with MST1, the control group transfected with empty vector, small interfering RNA then treated with CDDP after 36 hours of use flow cytometry was used to detect Annexin-V staining cell apoptosis.C. HCT116 p53+/+ and HCT116 p53-/- cells transfected with MST1, the control group were transfected with small interfering RNA, then treated with CDDP after 48 hours were detected by flow cytometry with Annexin-V staining of cell apoptosis in.D. U2OS cells transfected by MST1 plasmid and Sirt1 plasmid were transferred or empty the carrier by Etoposide. After 36 hours of treatment by flow cytometry to detect cell apoptosis by Annexin-V staining.
The effect of 2.1 MST1 on the deacetylation of p53 mediated by Sirt1
The cell lysate group were detected by Western blot method A. stable transfection of MST1 HCT116 p53+/+ cells and stably transfected with the empty vector, using antibodies including anti p53-k382 acetylation and anti p53 antibodies. The sample volume by reference 14-3-3 beta protein adjustment, so as to maintain consistent.B. HA-p53 transfected or FLAG-Sirt1 transfected and immune precipitate GFP-MST1 cells by Western blot, using antibodies including anti HA antibody and anti FLAG antibody.C. was transfected into p53, P300, Sirt1, Western blot was used to detect the cell lysate of MST1 plasmid 293T, the antibody of anti p53-k382 antibody acetylation.
How to enhance p53 acetylation by 2.2 MST1 and Sirt1
A. MST1 kinase in vitro experiment, the recombinant MST1 protein and its substrate GST-Sirt1 were incubated in the presence of 32P-ATP. The determination of.B. in vitro MST1 kinase assay fluorescent autoradiography by polyacrylamide gel electrophoresis for protein separation after reaction, active recombinant MST1 protein in the presence of 32P-ATP and Sirt1 protein fragment (P1, P2 P3), were incubated. The determination of.C. phosphorylation in vitro experiment of fluorescent autoradiography by polyacrylamide gel electrophoresis for protein separation after the reaction, the presence of MST1 protein and Sirt1 protein activity in non radioactive ATP cases were incubated and then phosphorylated experimental products and acetylated p53 incubation and deacetylation experiment. After reaction with proteins separated by polyacrylamide gel electrophoresis and Western blot was used to detect the anti p53-K382 antibody, acetylation antibody, anti GST antibody And anti Sirt1 antibody.
Results and conclusions
1.1 MST1 enhanced the transcriptional activity of p53 by inhibiting the activity of Sirt1.
In the 14*p53 gene, the expression of Sirt1 was inhibited by p53, while the wild type MST1 can significantly save the Sirt1 induced decrease of p53, but the ATP binding site mutation of the kinase activity of inactivation of MST1 (MST1 K59R) can save the Sirt1 induced decrease of p53. Similarly, Sirt1 inhibited p53 dependent p21 luciferase activity, while MST1 can reduce the expression of reversed Sirt1 induced p21. In summary, MST1 to promote p53 transcriptional activity through inhibition of Sirt1.
1.2 MST1 promotes apoptosis is dependent on p53 and Sirt1 can inhibit apoptosis induced by MST1.
U2OS cells overexpressing MST1 in p53 gene interfered under the condition, after treatment with Etoposide, reducing apoptosis. We also found that HCT116 in p53-/- cells with stable expression of MST1 can increase the number of cell apoptosis induced by Cisplatin, but MST1 HCT116 in p53+/+ cells of stable expression can increase the number of cell apoptosis induced by Cisplatin and, we also found that the disturbance of cell apoptosis induced by Cisplatin MST1 off in HCT116 p53+/+ cells was significantly reduced in HCT116 p53-/- cells apoptosis induced by Cisplatin interference cannot be dropped after MST1 was reduced. These experimental evidence of MST1 in DNA damage conditions promoting cell apoptosis is dependent on p53. and overexpressed in Sirt1 cells, MST1 mediated apoptosis will be reduced.
2.1 MST1 inhibits Sirt1 mediated p53 deacetylation.
We found that in vitro MST1 kinase assay MST1 cannot directly phosphorylate p53. and acetylated Western antibody test results using blot specific p53 in MST1 showed that the expression level of endogenous p53 cells increased acetyl. Then we use IP experiments show that MST1 and Sirt1 have direct interaction. Then, we observed the expression of the interaction of p53 and Sirt1 MST1 will be reduced. And the same, in cells overexpressing MST1 in Sirt1 mediated deacetylation of p53 is suppressed. In summary, MST1 inhibited Sirt1 mediated p53 deacetylation. We also found that can reduce Sirt1 mediated deacetylation of FOXO3 in vitro MST1, indicating that MST1 might regulate Sirt1 other substrates of biological activity.
2.2 MST1 increases p53 acetylation by phosphorylated Sirt1.
In vitro MST1 kinase assay using recombinant Sirt1 protein as substrate showed that Sirt1 can be phosphorylated by MST1. Then we use recombinant GST fusion protein respectively encoding 3 non overlapping regions of Sirt1 (peptide P1-P3) and points out that it is the phosphorylated region on Sirt1. The in vitro kinase assay shows that contains 489-747 article at the end of the amino acid fragment of C P3 is the main region of phosphorylation. In vitro phosphorylation and acetylation experiments, the phosphorylation of MST1 Sirt1 did reduce Sirt1 induced p53 deacetylation. Through the above experiments we elucidated the molecular mechanism of MST1 negative regulation by Sirt1 deacetylation activity to regulate the function of p53.

【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R329

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