It is well established that when mitochondrial respiration is impaired,the H+ATP synthase can function in reverse acting as an ATP hydrolase for maintaining the proton motive force[1].This process is regulated by an i...It is well established that when mitochondrial respiration is impaired,the H+ATP synthase can function in reverse acting as an ATP hydrolase for maintaining the proton motive force[1].This process is regulated by an inhibitor peptide called ATPase inhibitory factor 1 or IF1,a highly conserved nuclearly encoded protein[2].Since IF1 is highly expressed in most tumors,the significance of IF1 in tumor cells has also been widely studied[3].展开更多
TdT-interacting factor 1(TdIF1)is a ubiquitously expressed DNA-and protein-binding protein that directly binds to terminal deoxynucleotidyl transferase(TdT)polymerase.Little is known about the functional role of TdIF1...TdT-interacting factor 1(TdIF1)is a ubiquitously expressed DNA-and protein-binding protein that directly binds to terminal deoxynucleotidyl transferase(TdT)polymerase.Little is known about the functional role of TdIF1 in cancer cellular signaling,nor has it previously been identified as aberrant in any type of cancer.We report here for the first time that TdIF1 is abundantly expressed in clinical lung cancer patients and that high expression of TdIF1 is associated with poor patient prognosis.We further established that TdIF1 is highly expressed in human non-small cell lung cancer(NSCLC)cell lines compared to a normal lung cell line.shRNA-mediated gene silencing of TdIF1 resulted in the suppression of proliferation and anchorage-independent colony formation of the A549 adenocarcinoma cell line.Moreover,when these TdIF1-silenced cells were used to establish a mouse xenograft model of human NSCLC,tumor size was greatly reduced.These data suggest that TdIF1 is a potent regulator of lung tumor development.Several cell cycle-related and tumor growth signaling pathways,including the p53 and HDAC1/2 pathways,were identified as participating in the TdIF1 signaling network by in silico analysis.Microarray,transcriptome and protein-level analyses validated p53 and HDAC1/2 modulation upon TdIF1 downregulation in an NSCLC cellular model.Moreover,several other cell cycle regulators were affected at the transcript level by TdIF1 silencing,including an increase in CDKN1A/p21 transcripts.Taken together,these results indicate that TdIF1 is a bona fide tumor-promoting factor in NSCLC and a potential target for therapy.展开更多
基金Key Program of National Natural Science Foundation of China(U1432248)National Natural Science Foundation of China(11775280)National Natural Science Foundation of China(11665003)。
文摘It is well established that when mitochondrial respiration is impaired,the H+ATP synthase can function in reverse acting as an ATP hydrolase for maintaining the proton motive force[1].This process is regulated by an inhibitor peptide called ATPase inhibitory factor 1 or IF1,a highly conserved nuclearly encoded protein[2].Since IF1 is highly expressed in most tumors,the significance of IF1 in tumor cells has also been widely studied[3].
基金This study was supported by grants from the Natural Science Foundation of China(NSFC,No.81673009,81803064)the Jiangxi Provincial Natural Science Foundation(20161BBG70061)the Canadian Institutes of Health Research(CIHR).
文摘TdT-interacting factor 1(TdIF1)is a ubiquitously expressed DNA-and protein-binding protein that directly binds to terminal deoxynucleotidyl transferase(TdT)polymerase.Little is known about the functional role of TdIF1 in cancer cellular signaling,nor has it previously been identified as aberrant in any type of cancer.We report here for the first time that TdIF1 is abundantly expressed in clinical lung cancer patients and that high expression of TdIF1 is associated with poor patient prognosis.We further established that TdIF1 is highly expressed in human non-small cell lung cancer(NSCLC)cell lines compared to a normal lung cell line.shRNA-mediated gene silencing of TdIF1 resulted in the suppression of proliferation and anchorage-independent colony formation of the A549 adenocarcinoma cell line.Moreover,when these TdIF1-silenced cells were used to establish a mouse xenograft model of human NSCLC,tumor size was greatly reduced.These data suggest that TdIF1 is a potent regulator of lung tumor development.Several cell cycle-related and tumor growth signaling pathways,including the p53 and HDAC1/2 pathways,were identified as participating in the TdIF1 signaling network by in silico analysis.Microarray,transcriptome and protein-level analyses validated p53 and HDAC1/2 modulation upon TdIF1 downregulation in an NSCLC cellular model.Moreover,several other cell cycle regulators were affected at the transcript level by TdIF1 silencing,including an increase in CDKN1A/p21 transcripts.Taken together,these results indicate that TdIF1 is a bona fide tumor-promoting factor in NSCLC and a potential target for therapy.
