G蛋白偶联受体激酶5对细胞凋亡的调节及其机制研究
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摘要
G蛋白偶联受体(G-protein-coupled receptor, GPCR)是种类最多的细胞表面受体超家族,介导多种多样的配体信号,包括神经递质、激素、气味及其它小分子,同时也介导多种药物的活性。G蛋白偶联受体激酶(G-protein-coupled receptor kinases, GRKs)是调节GPCR的一类关键的丝苏氨酸激酶。当受体被活化后,GRK通过结合并迅速磷酸化受体胞内段,抑制受体的持续激活,导致受体的脱敏,并在其后发生的受体内吞和信号转导中起着重要作用。GRK有七种亚型,分为三个亚家族。其中GRK5广泛分布于全身多种器官,尤其高表达于心脏和肺,也广泛分布于骨骼肌,脑等器官,对多种GPCR具有选择性的调节作用。GRK起初被认为仅仅是GPCR的负性调控因子,然而不少证据表明,些GRK亚型,尤其是GRK5,可能具有新的功能。GRK5能够结合并调节胞浆中多种非受体底物,有特殊的核定位信号序列(Nuclear Location Sequence, NLS),能发生细胞核—胞浆的穿梭,并具有结合和影响转录因子的能力。此外研究提示GRK5在细胞周期的控制和细胞凋亡等重要的生理过程中也具有关键的调节作用,然而具体作用途径和影响方式有待进一步的研究。
肿瘤抑制因子p53调节了一系列重要生理过程,包括DNA损伤引起的细胞凋亡,细胞周期阻滞,细胞增殖,分化和衰老等等。p53蛋白水平的调节是影响其作用的重要途径之一,基础状态下p53主要通过泛素化和蛋白酶体降解途径维持在较低蛋白水平,p53的磷酸化对其稳定性起着重要的调节作用。我们的工作研究了GRK5在DNA损伤导致的细胞凋亡过程中的作用,以及GRK5对p53的调控机制。主要实验结果显示：
1. GRK5能够结合并磷酸化p53的55位苏氨酸,促进p53的泛素化—蛋白酶体途径降解过程。我们用免疫沉淀和体外结合实验证实,GRK5能够特异性结合p53；采用放射性同位素标记的体外激酶实验发现GRK5能够磷酸化p53,采用多种p53磷酸化位点特异性的抗体通过Western免疫印迹筛选后发现,GRK5能够特异性磷酸化p53的55位苏氨酸。突变该位点为丙氨酸或采用GRK5激酶活性缺失的突变体GRK5 K215R,以及使用GRK家族的抑制剂heparin均能有效抑制GRK5对p53的55位苏氨酸磷酸化。在细胞实验中,GRK5小干扰RNA (siRNA)处理能够明显减弱肿瘤细胞内源的p53的55位苏氨酸磷酸化并增强内源p53蛋白水平；过表达GRK5则能够增强53的55位苏氨酸磷酸化并降低内源p53蛋白水平,同时GRK5激酶活性缺失的突变体无此作用。我们发现GRK5 siRNA处理并未减弱p53的转录水平,采用Mdm2 siRNA,或药物处理阻断p53-Mdm2相互作用,或蛋白酶体抑制剂三种方式阻断p53的降解途径之后,GRK5 siRNA就不能改变p53的蛋白水平,提示GRK5通过促进了p53转录后的降解过程影响了p53的表达。并且这一作用是依赖于GRK5激酶活性的,过表达GRK5的肿瘤细胞中外转或者内源的p53蛋白水平均有降低,而GRK5激酶活性缺失的突变体无此作用。我们进一步发现,过表达GRK5促进了p53的泛素化和降解,突变p53的55位苏氨酸为丙氨酸,或使用GRK5的激酶活性缺失突变体则无此作用。同时过表达GRK5也加快了p53的半衰期,GRK5 siRNA处理则相反。这些结果表明GRK5通过磷酸化p53的55位苏氨酸加速了p53的泛素—蛋白酶体降解过程。
2. GRK5调节了p53依赖的细胞凋亡和G1期阻滞(G1 arrest)。我们用顺铂等致DNA损伤药物处理肿瘤细胞,分析细胞凋亡情况后发现,GRK5 siRNA处理能够促进DNA损伤引起的细胞凋亡,同时增强p53蛋白水平及下游基因Bax、p21的表达。过表达GRK5能在p53+／+肿瘤细胞系中抑制凋亡,并依赖于其激酶活性。而在p53-／-细胞系中过表达GRK5或GRK5 K215R对凋亡没有明显影响；只有共转染p53时,GRK5才能明显抑制凋亡反应,激酶活性缺失的突变体GRK5 K215R则无此作用,提示GRK5主要通过p53调节了凋亡过程,并且依赖于其激酶活性。对细胞周期以及细胞增殖分析的实验发现,GRK5 siRNA处理促使肿瘤细胞停滞在G1期,并抑制细胞增殖速度；相反,在p53-／-细胞系中共转染p53与GRK5或GRK5 K215R时,转染GRK5的细胞较激酶活性缺失突变体增殖速、度加快,而在突变p53的55位苏氨酸为丙氨酸后,共转染GRK5或GRK5 K215R对细胞增殖的影响无差异。这些结果提示GRK5通过磷酸化影响了p53促进细胞凋亡和G1期阻滞的生理功能。
3.在GRK5基因敲除小鼠中,我们检测了包括心脏,肝脏,脾脏,肺、肾脏以及胸腺组织内源p53蛋白水平,与对照组相比p53的蛋白水平,以及p53下游基因Bax的表达均高于正常小鼠。γ射线辐射提取胸腺细胞检测凋亡情况,GRK5基因敲除小鼠与对照组相比明显提高。这提示GRK5可能在整体水平调节了p53的表达及下游功能。
本研究首次证明：1、GRK5能够特异性结合p53并磷酸化p53的55位苏氨酸,从而促进p53的泛素化—蛋白酶体途径降解过程。2、GRK5能够抑制p53依赖的细胞凋亡和G1期阻滞。3、在GRK5基因敲除小鼠中,p53的蛋白水平以及DNA损伤导致的胸腺细胞凋亡均有升高。我们的研究首次发现p53是GRK5的底物,GRK5能够在细胞以及整体水平调节p53的水平,从而影响p53依赖的细胞凋亡,细胞周期调控等多种重要功能。我们的实验结果表明GRK5具有调节GPCR之外的新功能,对于研究GRK家族调节膜受体之外的其他底物具有借鉴意义。
G protein-coupled receptors (GPCRs), the largest family of membrane receptors, transduce a large number of extracellular signals including hormones, neurotransmitters, odors and drugs to the interior of cells. G-protein-coupled receptor kinases (GRKs) comprise a family of serine/threonine protein kinases that bind and phosphorylate cytoplasmic domain of GPCRs upon agonist challenge, thus inhibit the persisting activation of receptors, mediate desensitization of GPCR signaling, and play an important role in the following internalization and signaling of GPCRs. Seven isoforms of GRKs (GRK1-7) have been identified, divided into three subfamilies. Being the best-characterized member of the GRK4 subfamily, GRK5 is found most abundantly in heart and lung, while expressed wildly in brain, musle and peripheral tissues. To this day, a variety of GPCRs have been found to be regulated by GRK5 selectively. Besides their well-known role as negetive regulator of GPCRs, there might be additional physiological significance of GRKs. GRK5 has been also reported to interact with and regulate nonreceptor substrates, have a functional nuclear localization sequence (NLS), capable of processing nuclear-cytoplasmic shuttling and regulate transcriptional factors. Furthermore, recent evidence indicates that members of GRK family may also serve as potential contributors of physiological processes, such as apoptosis and cell cycle control. However, detailed knowledge of the molecular mechanisms of these regulation remains to be investigated.
The tumor suppressor p53 primarily functions as a transcriptional factor and mediates a variety of downstream functions, including cell-cycle arrest or apoptotic cell death in response to DNA damage, cell growth, differentiation, tumorigenesis and senescence. The regulation of p53 level is important to its function. In non-stressed cells, p53 is kept at low levels by ubiquitination and following proteolysis. Phosphorylation of p53 is crucial for the regulation of p53 stabilization and activation. Our current study investigated the effect of GRK5 on apoptotic death in response to DNA damage, and revealed a novel function for GRK5 in the regulation of p53 through its kinase activity. Our results showed that:
1. GRK5 interacts with and phosphorylate p53 at Thr55, resulting in p53 degradation. We demonstrated that GRK5 can interact and phosphorylate p53 at Thr55 in vitro and in vivo. Substitution of Thr55 with an alanine residue (T55A), or using heparin, the inhibitor of GRK family, abolish the phosphorylation notablely. Treatment with GRK5 siRNA lead to decrease in the phosphorylation of endogenous p53 at Thr55, and increase in the protein level of p53, while overexpression of GRK 5 lead to the opposite effect. The p53 mRNA level was not altered by GRK5 siRNA. when the Mdm2-ubiquitin-proteasome degradation system was blocked, the effect of GRK5 siRNA on p53 level was eliminated, indicating that GRK5 regulates p53 level via Mdm2-mediated degradation. We also found that overexpression of GRK5, but not GRK5 kinase dead mutant, increased ubiquitination levels of p53, which can be abolished by substitution of Thr55 with an alanine. Furthermore, the degradation rate of p53 was increased in cells overexpressing GRK5, while treatment with GRK5 siRNA lead to the opposite effect. These results suggesting that GRK5 promotes ubiquitination and proteolysis of p53 via phosphorylation.
2. GRK5 regulated p53-dependent apoptosis and G1 arrest. We found that treatment of GRK5 siRNA increased the incidence of tumor cell apoptosis in response to DNA damage. Overexpression of GRK5 inhibite apoptosis in p53+/+cells, but not in p53-/-cells, indicating GRK5 regulates apoptosis mainly through p53. Overexpression of GRK5 kinase dead mutant had no such effect, suggesting the regulation of apoptosis was kinase activity-dependent. We also analysed the role of GRK5 on cell cycle and proliferation. Treatment of GRK5 siRNA resulted in G1 phase arrest and inhibition of cellproliferation. On the contrary, overexpression of GRK5 promoted cell proliferation, which was dependent on p53 phosphorylation. These data suggested that GRK5 regulates apoptosis and cell cycle, at least in part, through p53 phosphorylation.
3. Increased expression of p53 and p53 target gene Bax was found in multiple organs of GRK5 knock out mice.In addition, whole-body y-irradiation resulted in a higher apoptosis percentage in thymocytes of GRK5 knockout mice, which support an essential role for GRK5 as a negative regulator of p53 under physiological conditions.
Thus we describe a previously unknown function of GRK5, a subunit of GRK family, as a regulator of tumor suprossor p53.We found that GRK5 could regulate p53-mediated apoptosis in response to DNA damage. GRK5 interacts with and phosphorylate p53 at Thr55 in vitro and in vivo. The phosphorylation by GRK5 results in p53 degradation and affects cell G1 arrest and proliferation. Moreover, in mutiple tissue types of the GRK5 knock out mice, we found an increased level of p53. IR induced apoptosis was also enhanced in thymus cells of GRK5 knock out mice. Thus our results uncovered a novel function for GRK5 as a inhibitor of p53 and elucidate its function as a regulator of apoptosis and cell cycle.
肿瘤抑制因子p53调节了一系列重要生理过程,包括DNA损伤引起的细胞凋亡,细胞周期阻滞,细胞增殖,分化和衰老等等。p53蛋白水平的调节是影响其作用的重要途径之一,基础状态下p53主要通过泛素化和蛋白酶体降解途径维持在较低蛋白水平,p53的磷酸化对其稳定性起着重要的调节作用。我们的工作研究了GRK5在DNA损伤导致的细胞凋亡过程中的作用,以及GRK5对p53的调控机制。主要实验结果显示：
1. GRK5能够结合并磷酸化p53的55位苏氨酸,促进p53的泛素化—蛋白酶体途径降解过程。我们用免疫沉淀和体外结合实验证实,GRK5能够特异性结合p53；采用放射性同位素标记的体外激酶实验发现GRK5能够磷酸化p53,采用多种p53磷酸化位点特异性的抗体通过Western免疫印迹筛选后发现,GRK5能够特异性磷酸化p53的55位苏氨酸。突变该位点为丙氨酸或采用GRK5激酶活性缺失的突变体GRK5 K215R,以及使用GRK家族的抑制剂heparin均能有效抑制GRK5对p53的55位苏氨酸磷酸化。在细胞实验中,GRK5小干扰RNA (siRNA)处理能够明显减弱肿瘤细胞内源的p53的55位苏氨酸磷酸化并增强内源p53蛋白水平；过表达GRK5则能够增强53的55位苏氨酸磷酸化并降低内源p53蛋白水平,同时GRK5激酶活性缺失的突变体无此作用。我们发现GRK5 siRNA处理并未减弱p53的转录水平,采用Mdm2 siRNA,或药物处理阻断p53-Mdm2相互作用,或蛋白酶体抑制剂三种方式阻断p53的降解途径之后,GRK5 siRNA就不能改变p53的蛋白水平,提示GRK5通过促进了p53转录后的降解过程影响了p53的表达。并且这一作用是依赖于GRK5激酶活性的,过表达GRK5的肿瘤细胞中外转或者内源的p53蛋白水平均有降低,而GRK5激酶活性缺失的突变体无此作用。我们进一步发现,过表达GRK5促进了p53的泛素化和降解,突变p53的55位苏氨酸为丙氨酸,或使用GRK5的激酶活性缺失突变体则无此作用。同时过表达GRK5也加快了p53的半衰期,GRK5 siRNA处理则相反。这些结果表明GRK5通过磷酸化p53的55位苏氨酸加速了p53的泛素—蛋白酶体降解过程。
2. GRK5调节了p53依赖的细胞凋亡和G1期阻滞(G1 arrest)。我们用顺铂等致DNA损伤药物处理肿瘤细胞,分析细胞凋亡情况后发现,GRK5 siRNA处理能够促进DNA损伤引起的细胞凋亡,同时增强p53蛋白水平及下游基因Bax、p21的表达。过表达GRK5能在p53+／+肿瘤细胞系中抑制凋亡,并依赖于其激酶活性。而在p53-／-细胞系中过表达GRK5或GRK5 K215R对凋亡没有明显影响；只有共转染p53时,GRK5才能明显抑制凋亡反应,激酶活性缺失的突变体GRK5 K215R则无此作用,提示GRK5主要通过p53调节了凋亡过程,并且依赖于其激酶活性。对细胞周期以及细胞增殖分析的实验发现,GRK5 siRNA处理促使肿瘤细胞停滞在G1期,并抑制细胞增殖速度；相反,在p53-／-细胞系中共转染p53与GRK5或GRK5 K215R时,转染GRK5的细胞较激酶活性缺失突变体增殖速、度加快,而在突变p53的55位苏氨酸为丙氨酸后,共转染GRK5或GRK5 K215R对细胞增殖的影响无差异。这些结果提示GRK5通过磷酸化影响了p53促进细胞凋亡和G1期阻滞的生理功能。
3.在GRK5基因敲除小鼠中,我们检测了包括心脏,肝脏,脾脏,肺、肾脏以及胸腺组织内源p53蛋白水平,与对照组相比p53的蛋白水平,以及p53下游基因Bax的表达均高于正常小鼠。γ射线辐射提取胸腺细胞检测凋亡情况,GRK5基因敲除小鼠与对照组相比明显提高。这提示GRK5可能在整体水平调节了p53的表达及下游功能。
本研究首次证明：1、GRK5能够特异性结合p53并磷酸化p53的55位苏氨酸,从而促进p53的泛素化—蛋白酶体途径降解过程。2、GRK5能够抑制p53依赖的细胞凋亡和G1期阻滞。3、在GRK5基因敲除小鼠中,p53的蛋白水平以及DNA损伤导致的胸腺细胞凋亡均有升高。我们的研究首次发现p53是GRK5的底物,GRK5能够在细胞以及整体水平调节p53的水平,从而影响p53依赖的细胞凋亡,细胞周期调控等多种重要功能。我们的实验结果表明GRK5具有调节GPCR之外的新功能,对于研究GRK家族调节膜受体之外的其他底物具有借鉴意义。
G protein-coupled receptors (GPCRs), the largest family of membrane receptors, transduce a large number of extracellular signals including hormones, neurotransmitters, odors and drugs to the interior of cells. G-protein-coupled receptor kinases (GRKs) comprise a family of serine/threonine protein kinases that bind and phosphorylate cytoplasmic domain of GPCRs upon agonist challenge, thus inhibit the persisting activation of receptors, mediate desensitization of GPCR signaling, and play an important role in the following internalization and signaling of GPCRs. Seven isoforms of GRKs (GRK1-7) have been identified, divided into three subfamilies. Being the best-characterized member of the GRK4 subfamily, GRK5 is found most abundantly in heart and lung, while expressed wildly in brain, musle and peripheral tissues. To this day, a variety of GPCRs have been found to be regulated by GRK5 selectively. Besides their well-known role as negetive regulator of GPCRs, there might be additional physiological significance of GRKs. GRK5 has been also reported to interact with and regulate nonreceptor substrates, have a functional nuclear localization sequence (NLS), capable of processing nuclear-cytoplasmic shuttling and regulate transcriptional factors. Furthermore, recent evidence indicates that members of GRK family may also serve as potential contributors of physiological processes, such as apoptosis and cell cycle control. However, detailed knowledge of the molecular mechanisms of these regulation remains to be investigated.
The tumor suppressor p53 primarily functions as a transcriptional factor and mediates a variety of downstream functions, including cell-cycle arrest or apoptotic cell death in response to DNA damage, cell growth, differentiation, tumorigenesis and senescence. The regulation of p53 level is important to its function. In non-stressed cells, p53 is kept at low levels by ubiquitination and following proteolysis. Phosphorylation of p53 is crucial for the regulation of p53 stabilization and activation. Our current study investigated the effect of GRK5 on apoptotic death in response to DNA damage, and revealed a novel function for GRK5 in the regulation of p53 through its kinase activity. Our results showed that:
1. GRK5 interacts with and phosphorylate p53 at Thr55, resulting in p53 degradation. We demonstrated that GRK5 can interact and phosphorylate p53 at Thr55 in vitro and in vivo. Substitution of Thr55 with an alanine residue (T55A), or using heparin, the inhibitor of GRK family, abolish the phosphorylation notablely. Treatment with GRK5 siRNA lead to decrease in the phosphorylation of endogenous p53 at Thr55, and increase in the protein level of p53, while overexpression of GRK 5 lead to the opposite effect. The p53 mRNA level was not altered by GRK5 siRNA. when the Mdm2-ubiquitin-proteasome degradation system was blocked, the effect of GRK5 siRNA on p53 level was eliminated, indicating that GRK5 regulates p53 level via Mdm2-mediated degradation. We also found that overexpression of GRK5, but not GRK5 kinase dead mutant, increased ubiquitination levels of p53, which can be abolished by substitution of Thr55 with an alanine. Furthermore, the degradation rate of p53 was increased in cells overexpressing GRK5, while treatment with GRK5 siRNA lead to the opposite effect. These results suggesting that GRK5 promotes ubiquitination and proteolysis of p53 via phosphorylation.
2. GRK5 regulated p53-dependent apoptosis and G1 arrest. We found that treatment of GRK5 siRNA increased the incidence of tumor cell apoptosis in response to DNA damage. Overexpression of GRK5 inhibite apoptosis in p53+/+cells, but not in p53-/-cells, indicating GRK5 regulates apoptosis mainly through p53. Overexpression of GRK5 kinase dead mutant had no such effect, suggesting the regulation of apoptosis was kinase activity-dependent. We also analysed the role of GRK5 on cell cycle and proliferation. Treatment of GRK5 siRNA resulted in G1 phase arrest and inhibition of cellproliferation. On the contrary, overexpression of GRK5 promoted cell proliferation, which was dependent on p53 phosphorylation. These data suggested that GRK5 regulates apoptosis and cell cycle, at least in part, through p53 phosphorylation.
3. Increased expression of p53 and p53 target gene Bax was found in multiple organs of GRK5 knock out mice.In addition, whole-body y-irradiation resulted in a higher apoptosis percentage in thymocytes of GRK5 knockout mice, which support an essential role for GRK5 as a negative regulator of p53 under physiological conditions.
Thus we describe a previously unknown function of GRK5, a subunit of GRK family, as a regulator of tumor suprossor p53.We found that GRK5 could regulate p53-mediated apoptosis in response to DNA damage. GRK5 interacts with and phosphorylate p53 at Thr55 in vitro and in vivo. The phosphorylation by GRK5 results in p53 degradation and affects cell G1 arrest and proliferation. Moreover, in mutiple tissue types of the GRK5 knock out mice, we found an increased level of p53. IR induced apoptosis was also enhanced in thymus cells of GRK5 knock out mice. Thus our results uncovered a novel function for GRK5 as a inhibitor of p53 and elucidate its function as a regulator of apoptosis and cell cycle.
引文
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