钙调神经磷酸酶(calcineurin,CN)作为机体中的一种丝/苏氨酸磷酸酶,在关键的生物学过程中发挥着重要作用.RCANs(regulators of calcineurin)是CN的一类内源调节因子,其家族成员在细胞中能够通过与CN在结构上的相互结合,起到调节CN活性...钙调神经磷酸酶(calcineurin,CN)作为机体中的一种丝/苏氨酸磷酸酶,在关键的生物学过程中发挥着重要作用.RCANs(regulators of calcineurin)是CN的一类内源调节因子,其家族成员在细胞中能够通过与CN在结构上的相互结合,起到调节CN活性的作用.而近来研究发现,该调节因子还可参与到CN-NFAT信号通路中发挥功能,从而与CN依赖的生理和病理过程的调控密切相关.因此,有必要对RCAN基因、RCANs蛋白与CN的相互作用以及该家族成员在病理条件下的重要功能作一个较为全面的综述,这些基础研究工作的进展将有助于为寻找新的疾病治疗方法和药物开辟新的途径.展开更多
拷贝数变异(Copy number variation,CNV)是染色体上发生的一种微结构变异,已引起越来越多研究者的关注。本课题组前期已获得猪13号染色体上的32个CNV区域(CNV region,CNVR),为了发掘CNVR内的基因信息,文章在线检索了上述CNVR内的基因并...拷贝数变异(Copy number variation,CNV)是染色体上发生的一种微结构变异,已引起越来越多研究者的关注。本课题组前期已获得猪13号染色体上的32个CNV区域(CNV region,CNVR),为了发掘CNVR内的基因信息,文章在线检索了上述CNVR内的基因并进行基因本体(Gene Ontology)分析。结果共发现236个基因,其中有注释基因169个,主要参与蛋白质水解、细胞粘附、大分子降解等生物过程。为了探索这些基因拷贝数变异的遗传规律,文章选择RCAN1(Regulators of calcineurin 1)基因为候选基因,利用QPCR方法在莱芜猪群中检测了该基因的拷贝数,并分析了CNV在莱芜猪3个家系中的遗传规律。结果表明,RCAN1基因在莱芜猪群体中存在拷贝数的缺失、重复现象,其拷贝数变异的遗传规律符合孟德尔遗传方式。展开更多
目的:探讨钙调磷酸酶调节因子1(regulator of calcineurin 1,RCAN1)基因在乳腺癌中的表达及临床意义。方法:检索Oncomine和GEO数据库中有关RCAN1的信息,并对所获取的数据资料挖掘并进行二次分析,对RCAN1在乳腺癌中的作用进行荟萃分析。...目的:探讨钙调磷酸酶调节因子1(regulator of calcineurin 1,RCAN1)基因在乳腺癌中的表达及临床意义。方法:检索Oncomine和GEO数据库中有关RCAN1的信息,并对所获取的数据资料挖掘并进行二次分析,对RCAN1在乳腺癌中的作用进行荟萃分析。结果:Oncomine数据库中共收集了454项不同类型RCAN1的研究结果,关于在肿瘤与对照组织中RCAN1表达有统计学差异的结果有64项,其中RCAN1表达增高的有20项,表达降低的有44项。涉及到乳腺癌的研究数据集共有13项。乳腺癌中高表达的研究有0项、低表达的有13项。共有6项研究,9个乳腺癌分型数据集涉及RCAN1在乳腺癌组织和正常组织中的表达,包括2 508例样本。在数据库中综合比较9项研究成果,发现与正常组织相比,RCAN1在乳腺癌中的表达量低于正常组织(P<0.05)。不仅如此,通过挖掘GEO数据库,发现低表达RCAN1的患者总体死亡率较高,高表达RCAN1的患者预后较好(P<0.05)。结论:通过深入挖掘Oncomine和GEO基因芯片数据库中肿瘤相关的基因信息,提示RCAN1的mRNA水平在乳腺癌组织中呈现低表达,并与乳腺癌预后相关,有望成为抗乳腺癌靶向治疗药物的重要靶点。展开更多
钙调神经磷酸酶调节蛋白(Regulator of calcineurin 1,RCAN1)作为与钙调神经磷酸酶(Calcineurin,Ca N)发生相互作用的内源性蛋白,在许多恶性肿瘤细胞中广泛表达,如小细胞肺癌、甲状腺癌、白血病、肝癌、恶性胶质细胞瘤、子宫内膜腺癌等...钙调神经磷酸酶调节蛋白(Regulator of calcineurin 1,RCAN1)作为与钙调神经磷酸酶(Calcineurin,Ca N)发生相互作用的内源性蛋白,在许多恶性肿瘤细胞中广泛表达,如小细胞肺癌、甲状腺癌、白血病、肝癌、恶性胶质细胞瘤、子宫内膜腺癌等。近年来研究显示,当RCAN1呈高表达状态时,可以通过多种途径来抑制肿瘤的增殖、分化、侵袭和转移,从而抑制肿瘤的进展。这些研究结果对患者的生存期和预后评估有着重要的指导作用,并对恶性肿瘤的治疗和干预奠定了一定的理论基础。展开更多
目的探讨Rcan2在结直肠癌组织中的表达及与临床病理的相互关系。方法方便收集该院2012年1月—2017年1月期间诊治的炎症性肠病20例、增生性息肉20例、腺瘤40例、结直肠癌及其癌旁正常组织80例,获取标本总RNA,q PCR测定Rcan2 m RNA表达水...目的探讨Rcan2在结直肠癌组织中的表达及与临床病理的相互关系。方法方便收集该院2012年1月—2017年1月期间诊治的炎症性肠病20例、增生性息肉20例、腺瘤40例、结直肠癌及其癌旁正常组织80例,获取标本总RNA,q PCR测定Rcan2 m RNA表达水平,对Rcan2 m RNA的差异表达与结直肠癌患者临床病理信息进行相关性分析。体外转染Rcan2基因于结直肠癌colo320DM细胞,MTT实验观察Rcan2过表达对肿瘤细胞增殖的影响。体外转染kras突变基因(G12V)于人结直肠癌细胞中,观察Rcan2基因的表达情况。结果结直肠癌组织中Rcan2 m RNA表达量(2.98±0.21)明显高于其他各组。Rcan2 m RNA的表达量与肿瘤大小密切相关(P<0.01)。Rcan2-pcdna3.1转染的细胞增长速度慢,OD值从10上升到14,而pcdna3.1转染的细胞增长速度快,OD值从12上升到18,过表达kras(G12V)抑制Rcan2基因表达。Rcan2相对表达量从2.8下降到1.1。结论这些发现提示Rcan2是一个潜在的结直肠癌诊断指标。展开更多
Noncompaction of the ventricular myocardium(NVM),the third most diagnosed cardiomyopathy,is characterized by prominent trabeculae and intratrabecular recesses.However,the genetic etiology of 40%–60%of NVM cases remai...Noncompaction of the ventricular myocardium(NVM),the third most diagnosed cardiomyopathy,is characterized by prominent trabeculae and intratrabecular recesses.However,the genetic etiology of 40%–60%of NVM cases remains unknown.Here,we identify two infants with NVM,in a nonconsanguineous family,with a typical clinical presentation of persistent bradycardia since the prenatal period.A homozygous missense variant(R223L)of RCAN family member 3(RCAN3)is detected in both infants using whole-exome sequencing.In the zebrafish model,marked cardiac dysfunction is detected in rcan3 deficiency(MO-rcan3^(ATG)-injected)and rcan^(−/−) embryos.Developmental dysplasia of both endocardial and myocardial layers is also detected in rcan3-deficient embryos.RCAN3 R223L variant mRNAs can not rescue heart defects caused by rcan3 knockdown or knockout;however,hRCAN3 mRNAs rescue these phenotypes.RNA-seq experiments show that several genes involved in cardiomyopathies are significantly regulated through multiple signaling pathways in the rcan3-knockdown zebrafish model.In human cardiomyocytes,RCAN3 deficiency results in reduced proliferation and increased apoptosis,together with an abnormal mitochondrial ultrastructure.Thus,we suggest that RCAN3 is a susceptibility gene for cardiomyopathies,especially NVM and that the R223L mutation is a potential loss-of-function variant.展开更多
体重及脂肪组织被认为受到能量稳态机制的严格调控,即脂肪细胞分泌的、显示机体脂肪含量的信号分子——瘦素通过下丘脑的信号通路对体重进行双向调控.近几十年来肥胖在全球暴发,肥胖个体中过量的瘦素并未抑制体重的增长,该现象被归因于&...体重及脂肪组织被认为受到能量稳态机制的严格调控,即脂肪细胞分泌的、显示机体脂肪含量的信号分子——瘦素通过下丘脑的信号通路对体重进行双向调控.近几十年来肥胖在全球暴发,肥胖个体中过量的瘦素并未抑制体重的增长,该现象被归因于"瘦素抵抗".然而最近有证据显示,肥胖发生过程中瘦素功能没有改变,瘦素抵抗不存在.因此体重是否受稳态调控存有争议.而本研究组发现一种依赖R c a n 2基因且不受瘦素抑制的增加摄食及体重的机制,伴有高脂肪食物时可导致体重快速增加进而产生肥胖,该发现可为肥胖的流行提供新的解释.展开更多
RCAN1, also known as DSCR1, is an endogenous regulator of calcineurin, a serine/threonine protein phosphatase that plays a critical role in many physiological processes. In this report, we demonstrate that p38a MAP ki...RCAN1, also known as DSCR1, is an endogenous regulator of calcineurin, a serine/threonine protein phosphatase that plays a critical role in many physiological processes. In this report, we demonstrate that p38a MAP kinase can phosphorylate RCAN1 at multiple sites in vitro and show that phospho-RCAN1 is a good protein substrate for calcineurin. In addition, we found that unphosphorylated RCANI noncompetitively inhibits calcineurin protein phosphatase activity and that the phosphorylation of RCAN1 by p38a MAP kinase decreases the binding affinity of RCAN1 for calcineurin. These findings reveal the molecular mechanism by which p38a MAP kinase regulates the function of RCAN1/calcineurin through phosphorylation.展开更多
It is widely accepted that body weight and adipose mass are tightly regulated by homeostatic mechanisms, in which leptin plays a critical role through hypothalamic pathways, and obesity is a result of homeostatic diso...It is widely accepted that body weight and adipose mass are tightly regulated by homeostatic mechanisms, in which leptin plays a critical role through hypothalamic pathways, and obesity is a result of homeostatic disorder. However, in C57BL/6J mice, we found that Rcan2 increases food intake and plays an important role in the develop- ment of age- and diet-induced obesity through a leptin-independent mechanism. RCAN2 was initially identified as a thyroid hormone （T3）-responsive gene in human fibroblasts. Expression of RCAN2 is regulated by T3 through the PI3K-Akt/PKB-mTOR-Rps6kbl signaling pathway. Intriguingly, both Rcan2-/- and Rps6kb1-/- mutations were re- ported to result in lean phenotypes in mice. In this study we compared the effects of these two mutations on growth and body weight in C57BL/6J mice. We observed reduced body weight and lower fat mass in both Rcan2-/- and Rps6kb1-/- mice compared to the wild-type mice, and we reported other differences unique to either the Rcan2-/- or Rps6kb1-/- mice. Firstly, loss of Rcan2 does not directly alter body length; however, Rcan2-/- mice exhibit reduced food intake. In contrast, Rps6kb1-/- mice exhibit abnormal embryonic development, which leads to smaller body size and reduced food intake in adulthood. Secondly, when fed a normal chow diet, Rcan2-/- mice weigh significantly more than Rps6kb1-/- mice, but both Rcan2-/- and Rps6kbl-/- mice develop similar amounts of epididymal fat. On a high-fat diet, Rcan2-/- mice gain body weight and fat mass at slower rates than Rps6kb1-/- mice. Finally, using the double-knockout mice （Rcan2-/- Rps6kb1-/-）, we demonstrate that concurrent loss of Rcan2and Rps6kbl has an additive effect on body weight reduction in C57BL/6J mice. Our data suggest that Rcan2 and Rps6kbl mutations both affect growth and body weight of mice, though likely through different mechanisms.展开更多
文摘钙调神经磷酸酶(calcineurin,CN)作为机体中的一种丝/苏氨酸磷酸酶,在关键的生物学过程中发挥着重要作用.RCANs(regulators of calcineurin)是CN的一类内源调节因子,其家族成员在细胞中能够通过与CN在结构上的相互结合,起到调节CN活性的作用.而近来研究发现,该调节因子还可参与到CN-NFAT信号通路中发挥功能,从而与CN依赖的生理和病理过程的调控密切相关.因此,有必要对RCAN基因、RCANs蛋白与CN的相互作用以及该家族成员在病理条件下的重要功能作一个较为全面的综述,这些基础研究工作的进展将有助于为寻找新的疾病治疗方法和药物开辟新的途径.
文摘拷贝数变异(Copy number variation,CNV)是染色体上发生的一种微结构变异,已引起越来越多研究者的关注。本课题组前期已获得猪13号染色体上的32个CNV区域(CNV region,CNVR),为了发掘CNVR内的基因信息,文章在线检索了上述CNVR内的基因并进行基因本体(Gene Ontology)分析。结果共发现236个基因,其中有注释基因169个,主要参与蛋白质水解、细胞粘附、大分子降解等生物过程。为了探索这些基因拷贝数变异的遗传规律,文章选择RCAN1(Regulators of calcineurin 1)基因为候选基因,利用QPCR方法在莱芜猪群中检测了该基因的拷贝数,并分析了CNV在莱芜猪3个家系中的遗传规律。结果表明,RCAN1基因在莱芜猪群体中存在拷贝数的缺失、重复现象,其拷贝数变异的遗传规律符合孟德尔遗传方式。
文摘目的:探讨钙调磷酸酶调节因子1(regulator of calcineurin 1,RCAN1)基因在乳腺癌中的表达及临床意义。方法:检索Oncomine和GEO数据库中有关RCAN1的信息,并对所获取的数据资料挖掘并进行二次分析,对RCAN1在乳腺癌中的作用进行荟萃分析。结果:Oncomine数据库中共收集了454项不同类型RCAN1的研究结果,关于在肿瘤与对照组织中RCAN1表达有统计学差异的结果有64项,其中RCAN1表达增高的有20项,表达降低的有44项。涉及到乳腺癌的研究数据集共有13项。乳腺癌中高表达的研究有0项、低表达的有13项。共有6项研究,9个乳腺癌分型数据集涉及RCAN1在乳腺癌组织和正常组织中的表达,包括2 508例样本。在数据库中综合比较9项研究成果,发现与正常组织相比,RCAN1在乳腺癌中的表达量低于正常组织(P<0.05)。不仅如此,通过挖掘GEO数据库,发现低表达RCAN1的患者总体死亡率较高,高表达RCAN1的患者预后较好(P<0.05)。结论:通过深入挖掘Oncomine和GEO基因芯片数据库中肿瘤相关的基因信息,提示RCAN1的mRNA水平在乳腺癌组织中呈现低表达,并与乳腺癌预后相关,有望成为抗乳腺癌靶向治疗药物的重要靶点。
文摘钙调神经磷酸酶调节蛋白(Regulator of calcineurin 1,RCAN1)作为与钙调神经磷酸酶(Calcineurin,Ca N)发生相互作用的内源性蛋白,在许多恶性肿瘤细胞中广泛表达,如小细胞肺癌、甲状腺癌、白血病、肝癌、恶性胶质细胞瘤、子宫内膜腺癌等。近年来研究显示,当RCAN1呈高表达状态时,可以通过多种途径来抑制肿瘤的增殖、分化、侵袭和转移,从而抑制肿瘤的进展。这些研究结果对患者的生存期和预后评估有着重要的指导作用,并对恶性肿瘤的治疗和干预奠定了一定的理论基础。
文摘目的探讨Rcan2在结直肠癌组织中的表达及与临床病理的相互关系。方法方便收集该院2012年1月—2017年1月期间诊治的炎症性肠病20例、增生性息肉20例、腺瘤40例、结直肠癌及其癌旁正常组织80例,获取标本总RNA,q PCR测定Rcan2 m RNA表达水平,对Rcan2 m RNA的差异表达与结直肠癌患者临床病理信息进行相关性分析。体外转染Rcan2基因于结直肠癌colo320DM细胞,MTT实验观察Rcan2过表达对肿瘤细胞增殖的影响。体外转染kras突变基因(G12V)于人结直肠癌细胞中,观察Rcan2基因的表达情况。结果结直肠癌组织中Rcan2 m RNA表达量(2.98±0.21)明显高于其他各组。Rcan2 m RNA的表达量与肿瘤大小密切相关(P<0.01)。Rcan2-pcdna3.1转染的细胞增长速度慢,OD值从10上升到14,而pcdna3.1转染的细胞增长速度快,OD值从12上升到18,过表达kras(G12V)抑制Rcan2基因表达。Rcan2相对表达量从2.8下降到1.1。结论这些发现提示Rcan2是一个潜在的结直肠癌诊断指标。
基金the National Key Research and Development Program of China(2022YFC2703302)the National Natural Science Foundation of China(82271692)+3 种基金the Sichuan Province Science and Technology Support Program,China(2022YFS0078)the Natural Science Foundation of Sichuan Province(2022NSFSC0782)the Fundamental Research Funds for the Central Universities(SCU2022F4080)Horizontal research project of Sichuan University(21H1095 and 21H1116).
文摘Noncompaction of the ventricular myocardium(NVM),the third most diagnosed cardiomyopathy,is characterized by prominent trabeculae and intratrabecular recesses.However,the genetic etiology of 40%–60%of NVM cases remains unknown.Here,we identify two infants with NVM,in a nonconsanguineous family,with a typical clinical presentation of persistent bradycardia since the prenatal period.A homozygous missense variant(R223L)of RCAN family member 3(RCAN3)is detected in both infants using whole-exome sequencing.In the zebrafish model,marked cardiac dysfunction is detected in rcan3 deficiency(MO-rcan3^(ATG)-injected)and rcan^(−/−) embryos.Developmental dysplasia of both endocardial and myocardial layers is also detected in rcan3-deficient embryos.RCAN3 R223L variant mRNAs can not rescue heart defects caused by rcan3 knockdown or knockout;however,hRCAN3 mRNAs rescue these phenotypes.RNA-seq experiments show that several genes involved in cardiomyopathies are significantly regulated through multiple signaling pathways in the rcan3-knockdown zebrafish model.In human cardiomyocytes,RCAN3 deficiency results in reduced proliferation and increased apoptosis,together with an abnormal mitochondrial ultrastructure.Thus,we suggest that RCAN3 is a susceptibility gene for cardiomyopathies,especially NVM and that the R223L mutation is a potential loss-of-function variant.
文摘体重及脂肪组织被认为受到能量稳态机制的严格调控,即脂肪细胞分泌的、显示机体脂肪含量的信号分子——瘦素通过下丘脑的信号通路对体重进行双向调控.近几十年来肥胖在全球暴发,肥胖个体中过量的瘦素并未抑制体重的增长,该现象被归因于"瘦素抵抗".然而最近有证据显示,肥胖发生过程中瘦素功能没有改变,瘦素抵抗不存在.因此体重是否受稳态调控存有争议.而本研究组发现一种依赖R c a n 2基因且不受瘦素抑制的增加摄食及体重的机制,伴有高脂肪食物时可导致体重快速增加进而产生肥胖,该发现可为肥胖的流行提供新的解释.
基金supported in part by Ministry of Science and Technology of China (Grant 2011CB910803)
文摘RCAN1, also known as DSCR1, is an endogenous regulator of calcineurin, a serine/threonine protein phosphatase that plays a critical role in many physiological processes. In this report, we demonstrate that p38a MAP kinase can phosphorylate RCAN1 at multiple sites in vitro and show that phospho-RCAN1 is a good protein substrate for calcineurin. In addition, we found that unphosphorylated RCANI noncompetitively inhibits calcineurin protein phosphatase activity and that the phosphorylation of RCAN1 by p38a MAP kinase decreases the binding affinity of RCAN1 for calcineurin. These findings reveal the molecular mechanism by which p38a MAP kinase regulates the function of RCAN1/calcineurin through phosphorylation.
基金Project supported by the National Natural Science Foundation of China(Nos.31140091 and 31371495)Shandong Natural Science Foundation(No.ZR2013CM040),China
文摘It is widely accepted that body weight and adipose mass are tightly regulated by homeostatic mechanisms, in which leptin plays a critical role through hypothalamic pathways, and obesity is a result of homeostatic disorder. However, in C57BL/6J mice, we found that Rcan2 increases food intake and plays an important role in the develop- ment of age- and diet-induced obesity through a leptin-independent mechanism. RCAN2 was initially identified as a thyroid hormone （T3）-responsive gene in human fibroblasts. Expression of RCAN2 is regulated by T3 through the PI3K-Akt/PKB-mTOR-Rps6kbl signaling pathway. Intriguingly, both Rcan2-/- and Rps6kb1-/- mutations were re- ported to result in lean phenotypes in mice. In this study we compared the effects of these two mutations on growth and body weight in C57BL/6J mice. We observed reduced body weight and lower fat mass in both Rcan2-/- and Rps6kb1-/- mice compared to the wild-type mice, and we reported other differences unique to either the Rcan2-/- or Rps6kb1-/- mice. Firstly, loss of Rcan2 does not directly alter body length; however, Rcan2-/- mice exhibit reduced food intake. In contrast, Rps6kb1-/- mice exhibit abnormal embryonic development, which leads to smaller body size and reduced food intake in adulthood. Secondly, when fed a normal chow diet, Rcan2-/- mice weigh significantly more than Rps6kb1-/- mice, but both Rcan2-/- and Rps6kbl-/- mice develop similar amounts of epididymal fat. On a high-fat diet, Rcan2-/- mice gain body weight and fat mass at slower rates than Rps6kb1-/- mice. Finally, using the double-knockout mice （Rcan2-/- Rps6kb1-/-）, we demonstrate that concurrent loss of Rcan2and Rps6kbl has an additive effect on body weight reduction in C57BL/6J mice. Our data suggest that Rcan2 and Rps6kbl mutations both affect growth and body weight of mice, though likely through different mechanisms.
