Cyclin-dependent kinase 1 （Cdkl）/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 （also known...Cyclin-dependent kinase 1 （Cdkl）/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 （also known as Cdk5rap3 and LZAP） potentiates DNA damage-induced cell death by modulating the G2/M checkpoint. More recently, Wang et al. （2007） found that C53/LZAP may function as a tumor suppressor by way of inhibiting NF-kB signaling. We re- port here the identification of C53 protein as a novel regulator of Cdkl activation. We found that knockdown of C53 protein causes delayed Cdkl activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 （Chkl and Chk2） is partially inhibited by C53 overexpression. Intriguingly, we found that C53 inter- acts with Chkl and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdkl activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chkl, C53 promotes Cdkl activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.展开更多
Esophageal adenocarcinoma is a major cause of cancer death in men in the developed world.Continuing poor outcomes with conventional therapies that predominantly target apoptosis pathways have lead to increasing intere...Esophageal adenocarcinoma is a major cause of cancer death in men in the developed world.Continuing poor outcomes with conventional therapies that predominantly target apoptosis pathways have lead to increasing interest in treatments that target the cell cycle.A large international effort has led to the development of a large number of inhibitors,which target cell cycle kinases,including cyclin-dependent kinases,Aurora kinases and polo-like kinase.Initial phase Ⅰ/Ⅱ trials in solid tumors have often demonstrated only modest clinical benefits of monotherapy.This may relate in part to a failure to identify the patient populations that will gain the most clinical benefit.Newer compounds lacking the side effect profile of first-generation compounds may show utility as adjunctive treatments targeted to an individual's predicted response to treatment.展开更多
The mitogen activated protein kinases-extracellular signal regulated kinases （MAPK-ERK） pathway is involved in regulation of multiple cellular processes including the cell cycle. In the present study using a Huh7 ce...The mitogen activated protein kinases-extracellular signal regulated kinases （MAPK-ERK） pathway is involved in regulation of multiple cellular processes including the cell cycle. In the present study using a Huh7 cell line Conl with an HCV replicon, we have shown that the MAPK-ERK pathway plays a significant role in the modulation of HCV replication and protein expression and might influence IFN-a signalling. Epithelial growth factor （EGF） was able to stimulate ERK activation and decreased HCV RNA load while a MAPK-ERK pathway inhibitor U0126 led to an elevated HCV RNA load and higher NS5A protein amounts in Conl cells. It could be further demonstrated that the inhibition of the MAPK-ERK pathway facilitated the translation directed by the HCV internal ribosome entry site. Consistently, a U0126 treatment enhanced activity of the HCV reporter replicon in transient transfeetion assays. Thus, the MAPK-ERK pathway plays an important role in the regulation of HCV gene expression and replication. In addition, cyclin-dependent kinases （CDKs） downstream of ERK may also be involved in the modulation of HCV replication since roscovitine, an inhibitor of CDKs had a similar effect to that of U0126. Modulation of the cell cycle progression by cell cycle inhibitor or RNAi resulted consistently in changes of HCV RNA levels. Further, the replication of HCV replicon in Conl cells was inhibited by IFN-~z. The inhibitory effect of IFN-CZ could be partly reversed by pre-incubation of Con-1 cells with inhibitors of the MAPK-ERK pathway and CDKs. It could be shown that the MAPK-ERK inhibitors are able to partially modulate the expression of interferon-stimulated genes.展开更多
文摘Cyclin-dependent kinase 1 （Cdkl）/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 （also known as Cdk5rap3 and LZAP） potentiates DNA damage-induced cell death by modulating the G2/M checkpoint. More recently, Wang et al. （2007） found that C53/LZAP may function as a tumor suppressor by way of inhibiting NF-kB signaling. We re- port here the identification of C53 protein as a novel regulator of Cdkl activation. We found that knockdown of C53 protein causes delayed Cdkl activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 （Chkl and Chk2） is partially inhibited by C53 overexpression. Intriguingly, we found that C53 inter- acts with Chkl and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdkl activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chkl, C53 promotes Cdkl activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.
基金Supported by UK National Institute of Health Research/Cancer Research Network and Research and Development Department of Wrightington Wigan and Leigh NHS Foundation Trust (to Ang YS)Wrightington Wigan and Leigh NHS Foundation Trust Cancer Therapy Fund (to Dibb M)
文摘Esophageal adenocarcinoma is a major cause of cancer death in men in the developed world.Continuing poor outcomes with conventional therapies that predominantly target apoptosis pathways have lead to increasing interest in treatments that target the cell cycle.A large international effort has led to the development of a large number of inhibitors,which target cell cycle kinases,including cyclin-dependent kinases,Aurora kinases and polo-like kinase.Initial phase Ⅰ/Ⅱ trials in solid tumors have often demonstrated only modest clinical benefits of monotherapy.This may relate in part to a failure to identify the patient populations that will gain the most clinical benefit.Newer compounds lacking the side effect profile of first-generation compounds may show utility as adjunctive treatments targeted to an individual's predicted response to treatment.
基金supported by a joint grant of Chinese Academy of Science and Deutsche Akademische Austausch Dienstthe National Basic Research Priorities Program ofChina(2009CB522501,2005CB522901,2007CB512901)
文摘The mitogen activated protein kinases-extracellular signal regulated kinases （MAPK-ERK） pathway is involved in regulation of multiple cellular processes including the cell cycle. In the present study using a Huh7 cell line Conl with an HCV replicon, we have shown that the MAPK-ERK pathway plays a significant role in the modulation of HCV replication and protein expression and might influence IFN-a signalling. Epithelial growth factor （EGF） was able to stimulate ERK activation and decreased HCV RNA load while a MAPK-ERK pathway inhibitor U0126 led to an elevated HCV RNA load and higher NS5A protein amounts in Conl cells. It could be further demonstrated that the inhibition of the MAPK-ERK pathway facilitated the translation directed by the HCV internal ribosome entry site. Consistently, a U0126 treatment enhanced activity of the HCV reporter replicon in transient transfeetion assays. Thus, the MAPK-ERK pathway plays an important role in the regulation of HCV gene expression and replication. In addition, cyclin-dependent kinases （CDKs） downstream of ERK may also be involved in the modulation of HCV replication since roscovitine, an inhibitor of CDKs had a similar effect to that of U0126. Modulation of the cell cycle progression by cell cycle inhibitor or RNAi resulted consistently in changes of HCV RNA levels. Further, the replication of HCV replicon in Conl cells was inhibited by IFN-~z. The inhibitory effect of IFN-CZ could be partly reversed by pre-incubation of Con-1 cells with inhibitors of the MAPK-ERK pathway and CDKs. It could be shown that the MAPK-ERK inhibitors are able to partially modulate the expression of interferon-stimulated genes.
文摘目的分析第10号染色体缺失的磷酸酶及张力蛋白(phosphatase and tensin homolog deleted on chro-mosome ten,PTEN)、基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)、细胞周期蛋白依赖性激酶抑制蛋白27(cyclin dependent kinase inhibitor protein 27,p27^(kip1))在乳腺癌组织中的表达情况,讨论其在乳腺癌发生、发展中的意义。方法选取2014年2月至2016年2月本院肿瘤科和乳腺外科收治的55例乳腺癌患者(乳腺癌组)和35例乳腺良性病变患者(乳腺良性病变组)为研究对象。采用免疫组织化学SP法检测入选患者PTEN、MMP-9、p27^(kip1)的表达水平。结果乳腺良性病变组PTEN和p27^(kip1)的表达率(82.86%,85.71%)均显著高于乳腺癌组(45.45%,43.64%)(P<0.05),MMP-9的表达率(42.86%)显著低于乳腺癌组(69.09%)(P<0.05)。乳腺癌组织中PTEN的表达与MMP-9的表达呈负相关(r=-0.587,P<0.05),与p27^(kip1)的表达呈正相关(r=0.532,P<0.05)。结论 PTEN与p27^(kip1)表达异常可能与乳腺癌的发生、发展及预后相关。MMP-9参与乳腺癌的发生、发展,可作为评估乳腺癌浸润和转移的生物学指标。
