Nedd1 (neural precursor cell expressed, developmentally down-regulated gene 1) is an evolutionarily conserved protein that has previously been characterized as a new member
Background： The E3 ubiquitin ligasc neural precursor cell expressed developmentally downregulated 4-1（N EDD4-1） negatively regulates phosphatase and tensin homolog deleted on chromosome 10 （PTEN） protein levels t...Background： The E3 ubiquitin ligasc neural precursor cell expressed developmentally downregulated 4-1（N EDD4-1） negatively regulates phosphatase and tensin homolog deleted on chromosome 10 （PTEN） protein levels through polyubiquitination and proteolysis, but its significance in lung cancer is still unclear. This study investigated the expression and the role of NEDD4-1 in tumor developnaent and chemosensitivity of lung adenocarcinoma （ADC）. Methods： We retrospectively investigated the expression and significance ofNEDD4-1, PTEN, and p-Akt proteins in 135 paired A DC and adjacent noncancerous tissue specimens using immunohistochemistry. Furthemaore, we evaluated the relationship between NEDD4-1 expression and clinicopathologic characteristics and prognosis. The effects of small interfering RNA against NEDD4-1 on proliferation and chemosensitivity were examined in A549 cells in vitro using 3- （4,5-dimethylthiazol-2-yl） -5-（3-carboxymethoxyphenyl） -2-（4-sulfophenyl）- 2H-tetrazoliunl method. The ability of migration and invasion ofA549 cells was tested by transwell assay. Moreover, reverse-transcription quantitative polymerase chain reaction and Western blotting analyses were used to determine the expression of NEDD4-1, PTEN, phosphoinositide 3-kinase （PI3K）/Akt activity, and its downstream target proteins. Results： NEDD4-1 protein was significantly upregulated in lung ADC tissues, whereas it was weak or negative in normal lung epithelial cells. The expression ofNEDD4-1 in ADC （78.5%, 106/135） was significantly much higher than that in adjacent normal lung tissue （ 13.3%, 29/135, P 〈 0.01）, and it was associated with lymph node metastasis, tumor-node-metastasis （TNM） stage, and chemotherapy resistance. PTEN expression was downregulated in lung ADC （60.7% vs. 100.0% in noncancerous specimens, P - 0.007）, and was negatively correlated with lymph node metastasis, histological variants, clinical stage, chemoresistance. In addition, expression of p-Akt in ADC tissues （71.1% 96/135） was much higher than that in adjacent lung epithelial cells （6.7%, 9/135, P 〈 0.01 ）. Kaplan-Meier and multivariate analysis demonstrated that expressions ofNEDD4-1 and PTEN were both independent risk factors for survival in patients with lung ADC. NEDD4-1 knockdown in vivo decreased proliferation, migration, and invasion and improved chemosensitivity to cisplatin and paclitaxel in A549 cells. NEDD4-1 knockdown also significantly enhanced PTEN expression and inhibited p-Akt activity and downstream target proteins. Conclusions： NEDD4-1 upregulation may contribute to the progression of lung ADC. NEDD4-1 may regulate the proliferation, invasion, migration, and chemoresistance of lung ADC cells through the P13K/Akt pathway, suggesting that it may be regarded as a therapeutic target for the treatment of lung ADC.展开更多
Acetaminophen(APAP)overdose is a major cause of liver injury.Neural precursor cell expressed developmentally downregulated 4—1(NEDD4-1)is an E3 ubiquitin ligase that has been implicated in the pathogenesis of numerou...Acetaminophen(APAP)overdose is a major cause of liver injury.Neural precursor cell expressed developmentally downregulated 4—1(NEDD4-1)is an E3 ubiquitin ligase that has been implicated in the pathogenesis of numerous liver diseases;however,its role in APAP-induced liver injury(AILI)is unclear.Thus,this study aimed to investigate the role of NEDD4-1 in the pathogenesis of AILI.We found that NEDD4-1 was dramatically downregulated in response to APAP treatment in mouse livers and isolated mouse hepatocytes.Hepatocyte-specific NEDD4-1 knockout exacerbated APAP-induced mitochondrial damage and the resultant hepatocyte necrosis and liver injury,while hepatocyte-specific NEDD4-1 overexpression mitigated these pathological events both in vivo and in vitro.Additionally,hepatocyte NEDD4-1 deficiency led to marked accumulation of voltage-dependent anion channel 1(VDAC1)and increased VDAC1 oligomerization.Furthermore,VDAC1 knockdown alleviated AILI and weakened the exacerbation of AILI caused by hepatocyte NEDD4-1 deficiency.Mechanistically,NEDD4-1 was found to interact with the PPTY motif of VDAC1 through its WW domain and regulate K48-linked ubiquitination and degradation of VDAC1.Our present study indicates that NEDD4-1 is a suppressor of AILI and functions by regulating the degradation of VDAC1.展开更多
文摘Nedd1 (neural precursor cell expressed, developmentally down-regulated gene 1) is an evolutionarily conserved protein that has previously been characterized as a new member
基金This work was supported by a grant from the National Natural Science Foundation of China （No. 81402185）.
文摘Background： The E3 ubiquitin ligasc neural precursor cell expressed developmentally downregulated 4-1（N EDD4-1） negatively regulates phosphatase and tensin homolog deleted on chromosome 10 （PTEN） protein levels through polyubiquitination and proteolysis, but its significance in lung cancer is still unclear. This study investigated the expression and the role of NEDD4-1 in tumor developnaent and chemosensitivity of lung adenocarcinoma （ADC）. Methods： We retrospectively investigated the expression and significance ofNEDD4-1, PTEN, and p-Akt proteins in 135 paired A DC and adjacent noncancerous tissue specimens using immunohistochemistry. Furthemaore, we evaluated the relationship between NEDD4-1 expression and clinicopathologic characteristics and prognosis. The effects of small interfering RNA against NEDD4-1 on proliferation and chemosensitivity were examined in A549 cells in vitro using 3- （4,5-dimethylthiazol-2-yl） -5-（3-carboxymethoxyphenyl） -2-（4-sulfophenyl）- 2H-tetrazoliunl method. The ability of migration and invasion ofA549 cells was tested by transwell assay. Moreover, reverse-transcription quantitative polymerase chain reaction and Western blotting analyses were used to determine the expression of NEDD4-1, PTEN, phosphoinositide 3-kinase （PI3K）/Akt activity, and its downstream target proteins. Results： NEDD4-1 protein was significantly upregulated in lung ADC tissues, whereas it was weak or negative in normal lung epithelial cells. The expression ofNEDD4-1 in ADC （78.5%, 106/135） was significantly much higher than that in adjacent normal lung tissue （ 13.3%, 29/135, P 〈 0.01）, and it was associated with lymph node metastasis, tumor-node-metastasis （TNM） stage, and chemotherapy resistance. PTEN expression was downregulated in lung ADC （60.7% vs. 100.0% in noncancerous specimens, P - 0.007）, and was negatively correlated with lymph node metastasis, histological variants, clinical stage, chemoresistance. In addition, expression of p-Akt in ADC tissues （71.1% 96/135） was much higher than that in adjacent lung epithelial cells （6.7%, 9/135, P 〈 0.01 ）. Kaplan-Meier and multivariate analysis demonstrated that expressions ofNEDD4-1 and PTEN were both independent risk factors for survival in patients with lung ADC. NEDD4-1 knockdown in vivo decreased proliferation, migration, and invasion and improved chemosensitivity to cisplatin and paclitaxel in A549 cells. NEDD4-1 knockdown also significantly enhanced PTEN expression and inhibited p-Akt activity and downstream target proteins. Conclusions： NEDD4-1 upregulation may contribute to the progression of lung ADC. NEDD4-1 may regulate the proliferation, invasion, migration, and chemoresistance of lung ADC cells through the P13K/Akt pathway, suggesting that it may be regarded as a therapeutic target for the treatment of lung ADC.
基金supported by the National Natural Science Foundation of China(Beijing,ChinaGrant Nos.32022084 and 32172927)。
文摘Acetaminophen(APAP)overdose is a major cause of liver injury.Neural precursor cell expressed developmentally downregulated 4—1(NEDD4-1)is an E3 ubiquitin ligase that has been implicated in the pathogenesis of numerous liver diseases;however,its role in APAP-induced liver injury(AILI)is unclear.Thus,this study aimed to investigate the role of NEDD4-1 in the pathogenesis of AILI.We found that NEDD4-1 was dramatically downregulated in response to APAP treatment in mouse livers and isolated mouse hepatocytes.Hepatocyte-specific NEDD4-1 knockout exacerbated APAP-induced mitochondrial damage and the resultant hepatocyte necrosis and liver injury,while hepatocyte-specific NEDD4-1 overexpression mitigated these pathological events both in vivo and in vitro.Additionally,hepatocyte NEDD4-1 deficiency led to marked accumulation of voltage-dependent anion channel 1(VDAC1)and increased VDAC1 oligomerization.Furthermore,VDAC1 knockdown alleviated AILI and weakened the exacerbation of AILI caused by hepatocyte NEDD4-1 deficiency.Mechanistically,NEDD4-1 was found to interact with the PPTY motif of VDAC1 through its WW domain and regulate K48-linked ubiquitination and degradation of VDAC1.Our present study indicates that NEDD4-1 is a suppressor of AILI and functions by regulating the degradation of VDAC1.
