It has been shown that oncoprotein p28GANK, which is consistently overexpressed in human hepatocellular carcinoma （HCC）, plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains uncle...It has been shown that oncoprotein p28GANK, which is consistently overexpressed in human hepatocellular carcinoma （HCC）, plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains unclear. Here, we demonstrated that p28GANK inhibits apoptosis in HCC cells induced by the endoplasmic reticulum （ER） stress. During ER stress, p28GANK enhances the unfolded protein response, promotes ER recovery from translational repression, and thereby facilitates cell＇s ability to cope with the stress conditions. Furthermore, p28GANK upregulates glucose-regulated protein 78 （GRP78）, a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. We also demonstrated that p28GANK increases p38 mitogen-activated protein kinase and Akt phosphorylation, and inhibits nuclear factor kappa B （NF-κB） activation under ER stress, which in turn contributes to GRP78 upregulation. Taken together, our results indicate that p28GANK inhibits ER stress-induced apoptosis in HCC cells, at least in part, by enhancing the adaptive response and GRP78 expression. We propose that p28GANK has potential implications for HCC progression under the ER stress conditions.展开更多
AIM: To observe the gene and protein expression changes of p28GANK in regenerating liver tissues, and to reveal the biological function of p28GANK on the regulation of liver regeneration.METHODS: One hundred and thirt...AIM: To observe the gene and protein expression changes of p28GANK in regenerating liver tissues, and to reveal the biological function of p28GANK on the regulation of liver regeneration.METHODS: One hundred and thirty two adult male Sprague-Dawley rats were selected, weighing 200-250 g,and divided randomly into sham operation (SO) group and partial hepatectomy (PH) group. Each group had eleven time points: 0, 2, 6, 12, 24, 30, 48, 72, 120, 168 and 240 h,six rats were in each time point. The rats were undergone 70 % PH under methoxyflurane anesthesia by resection of the anterior and left lateral lobes of the liver. SO was conducted by laparotomy plus slight mobilization of the liver without resection. Liver specimens were collected at the indicated time points after PH or SO. The expression level of p28GANK mRNA was determined by Northern blot as well as at protein level via immunohistochemical staining.The expressions of p28GANK mRNA in these tissues were analyzed by imaging analysis system of FLA-2000 FUJIFILM and one way analysis of variance. The protein expressions of p28GANK in these tissues were analyzed with Fromowitz'method and Rank sum test.RESULTS: The expression of p28GANK mRNA in bhe regenerating liver tissues possessed two transcripts, which were 1.5 kb and 1.0 kb. There was a significantly different expression patterns of p28GANK mRNA between SO and PH groups (P<0.01). The expression of p28GANK mRNA increased 2 h after PH, the peak time was 72 h (SO group: 163.83±1.4720; PH group: 510.5±17.0499, P<0.01). There was a significant difference in the 1.5 kb transcript, which decreased gradually after 72 hours. The protein expression of p28GANK was mainly in the cytoplasm of regenerating hepatocytes, and increased near the central region 24 h after PH, and became strongly positive at 48 h (+++, vs the other time points P<0.05),but decreased 72 h after PH.CONCLUSION: The expression of p28GANK mRNA increases in the early stage of rat liver regeneration, the protein expression of p28GANK is mainly in the cytoplasm of regenerating liver cells. It suggests that the gene of p28GANK may be an important regulatory and controlled factor involved in hepatocyte proliferation during liver regeneration.展开更多
p28^GANK （also known as PSMD 10, p28 and gankyrin） is an ankyrin repeat anti-apoptotic oncoprotein that is commonly overexpressed in hepatocellular carcinomas and increases the degradation of p53 and Rb. NF-IκB （n...p28^GANK （also known as PSMD 10, p28 and gankyrin） is an ankyrin repeat anti-apoptotic oncoprotein that is commonly overexpressed in hepatocellular carcinomas and increases the degradation of p53 and Rb. NF-IκB （nuclear factor-κB） is known to be sequestered in the cytoplasm by IκB （inhibitor of NF-κB） proteins [1, 2], but much less is known about the cytoplasmic retention of NF-κB by other cellular proteins. Here we show that p28^GANK inhibits NF-κB activity. As a nuclear-cytoplasmic shuttling protein, p28^GANK directly binds to NF-κB/RelA and exports RelA from nucleus through a chromosomal region maintenance-1 （CRM-1） dependent pathway, which results in the cytoplasmic retention of NF- κB/RelA. We demonstrate that all the ankyrin repeats of p28^GANK are required for the interaction with RelA and that the N terminus of p28^GANK, which contains the nuclear export sequence （NES）, is responsible for suppressing NF-κB/RelA nuclear translocation. These results suggest that overexpression of p28^GANK prevents the nuclear localization and inhibits the activity of NF-κB/RelA.展开更多
Part C:初期Gank攻与防3.守时的沉着如何做到?我们今天所说的防守是狭义的,是被动的防守。《孙子兵法》上说"善守者藏于九地之下"的意思是:善于防守的人很会隐藏自己、伪装自己,让敌人找不到自己的破绽,从而能很好的保护自己...Part C:初期Gank攻与防3.守时的沉着如何做到?我们今天所说的防守是狭义的,是被动的防守。《孙子兵法》上说"善守者藏于九地之下"的意思是:善于防守的人很会隐藏自己、伪装自己,让敌人找不到自己的破绽,从而能很好的保护自己,做到立于不败之地。DotA中面对促不及防的Gank该怎么办呢?突然和对手在树林里相遇了要怎么处理呢?如果你可以做到攻时骁勇,守时沉着也是很容易做到的:展开更多
文摘It has been shown that oncoprotein p28GANK, which is consistently overexpressed in human hepatocellular carcinoma （HCC）, plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains unclear. Here, we demonstrated that p28GANK inhibits apoptosis in HCC cells induced by the endoplasmic reticulum （ER） stress. During ER stress, p28GANK enhances the unfolded protein response, promotes ER recovery from translational repression, and thereby facilitates cell＇s ability to cope with the stress conditions. Furthermore, p28GANK upregulates glucose-regulated protein 78 （GRP78）, a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. We also demonstrated that p28GANK increases p38 mitogen-activated protein kinase and Akt phosphorylation, and inhibits nuclear factor kappa B （NF-κB） activation under ER stress, which in turn contributes to GRP78 upregulation. Taken together, our results indicate that p28GANK inhibits ER stress-induced apoptosis in HCC cells, at least in part, by enhancing the adaptive response and GRP78 expression. We propose that p28GANK has potential implications for HCC progression under the ER stress conditions.
文摘AIM: To observe the gene and protein expression changes of p28GANK in regenerating liver tissues, and to reveal the biological function of p28GANK on the regulation of liver regeneration.METHODS: One hundred and thirty two adult male Sprague-Dawley rats were selected, weighing 200-250 g,and divided randomly into sham operation (SO) group and partial hepatectomy (PH) group. Each group had eleven time points: 0, 2, 6, 12, 24, 30, 48, 72, 120, 168 and 240 h,six rats were in each time point. The rats were undergone 70 % PH under methoxyflurane anesthesia by resection of the anterior and left lateral lobes of the liver. SO was conducted by laparotomy plus slight mobilization of the liver without resection. Liver specimens were collected at the indicated time points after PH or SO. The expression level of p28GANK mRNA was determined by Northern blot as well as at protein level via immunohistochemical staining.The expressions of p28GANK mRNA in these tissues were analyzed by imaging analysis system of FLA-2000 FUJIFILM and one way analysis of variance. The protein expressions of p28GANK in these tissues were analyzed with Fromowitz'method and Rank sum test.RESULTS: The expression of p28GANK mRNA in bhe regenerating liver tissues possessed two transcripts, which were 1.5 kb and 1.0 kb. There was a significantly different expression patterns of p28GANK mRNA between SO and PH groups (P<0.01). The expression of p28GANK mRNA increased 2 h after PH, the peak time was 72 h (SO group: 163.83±1.4720; PH group: 510.5±17.0499, P<0.01). There was a significant difference in the 1.5 kb transcript, which decreased gradually after 72 hours. The protein expression of p28GANK was mainly in the cytoplasm of regenerating hepatocytes, and increased near the central region 24 h after PH, and became strongly positive at 48 h (+++, vs the other time points P<0.05),but decreased 72 h after PH.CONCLUSION: The expression of p28GANK mRNA increases in the early stage of rat liver regeneration, the protein expression of p28GANK is mainly in the cytoplasm of regenerating liver cells. It suggests that the gene of p28GANK may be an important regulatory and controlled factor involved in hepatocyte proliferation during liver regeneration.
基金Acknowledgments We thank Dr IM Verma （UCSD, USA） and Dr WC Greene （UCSF, USA） for the RelA, p50 and IKBct plasmids. Research was supported by grants from National Natural Science Foundation of China （30530790, 30620130434, 30428006 and 30500275）.
文摘p28^GANK （also known as PSMD 10, p28 and gankyrin） is an ankyrin repeat anti-apoptotic oncoprotein that is commonly overexpressed in hepatocellular carcinomas and increases the degradation of p53 and Rb. NF-IκB （nuclear factor-κB） is known to be sequestered in the cytoplasm by IκB （inhibitor of NF-κB） proteins [1, 2], but much less is known about the cytoplasmic retention of NF-κB by other cellular proteins. Here we show that p28^GANK inhibits NF-κB activity. As a nuclear-cytoplasmic shuttling protein, p28^GANK directly binds to NF-κB/RelA and exports RelA from nucleus through a chromosomal region maintenance-1 （CRM-1） dependent pathway, which results in the cytoplasmic retention of NF- κB/RelA. We demonstrate that all the ankyrin repeats of p28^GANK are required for the interaction with RelA and that the N terminus of p28^GANK, which contains the nuclear export sequence （NES）, is responsible for suppressing NF-κB/RelA nuclear translocation. These results suggest that overexpression of p28^GANK prevents the nuclear localization and inhibits the activity of NF-κB/RelA.
