Vascular endothelial growth factor （VEGF） is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization, trans...Vascular endothelial growth factor （VEGF） is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization, translation, and differential cellular localization of various isoforms. Recent advances in our understanding of post-transcriptional regulation of VEGF include identification of the stabilizing mRNA binding protein, HuR, and the discovery of internal ribosomal entry sites in the 5＇UTR of the VEGF mRNA. Monoclonal anti-VEGF antibody was recently approved for use in humans, but suffers from the need for high systemic doses. RNA interference （RNAi） technology is being used in vitro and in animal models with promising results. Here, we review the literature on post-transcriptional regulation of VEGF and describe recent progress in targeting these mechanisms for therapeutic benefit.展开更多
The RNA-binding proteins involved in regulation of mRNA post-transcriptional processing and translation control the fates of thousands of mRNA transcripts and basic cellular processes. The best studied of these, HuR, ...The RNA-binding proteins involved in regulation of mRNA post-transcriptional processing and translation control the fates of thousands of mRNA transcripts and basic cellular processes. The best studied of these, HuR, is well characterized as a mediator of mRNA stability and translation, and more recently, as a factor in nuclear functions such as pre-mRNA splicing. Due to HuR's role in regulating thousands of mRNA transcripts, including those for other RNA-binding proteins, HuR can act as a master regulator of cell survival and proliferation. HuR itself is subject to multiple post-translationa modifications including regulation of its nucleocytoplasmic distribution. However, the mechanisms that govern HuR levels in the cell have only recently begun to be defined. These mechanisms are critical to cell health, as it has become clear in recent years that aberrant expression of HuR can lead alternately to decreased cell viability or to promotion of pathological proliferation and invasiveness. HuR is expressed as alternate mRNAs that vary in their untranslated regions, leading to differences in transcript stability and translatability. Multiple transcription factors and modulators of mRNA stability that regulate HuR mRNA expression have been identified. In addition, translation of HuR is regulated by numerous microRNAs, several of which have been demonstrated to have anti-tumor properties due to their suppression of HuR expression. This review summarizes the current state of knowledge of the factors that regulate HuR expression, along with the circumstances under which these factors contribute to cancer and inflammation.展开更多
AIM: To investigate the expression of Hu R in pancreatic ductal adenocarcinoma(PDA) and to assess the effects of Hu R silencing on the expression of cyclooxygenase-2(COX-2) and heme oxygenase-1(HO-1) and the in vitro ...AIM: To investigate the expression of Hu R in pancreatic ductal adenocarcinoma(PDA) and to assess the effects of Hu R silencing on the expression of cyclooxygenase-2(COX-2) and heme oxygenase-1(HO-1) and the in vitro response to gemcitabine(GEM) treatment in pancreatic cell lines.METHODS: We compared the expression of Hu R,COX-2,and HO-1 in PDA and normal pancreatic tissueusing quantitative reverse transcription polymerase chain reaction(q RT-PCR) and western blot. In addition,the Hu R,COX-2 and HO-1 were analyzed in four types of cancer cell lines(Mia Paca2,Su.86.86,Capan-1,and Capan-2) with and without GEM treatment. Immunocytofluorescence analysis was used to investigate Hu R localization in cells. Cell viability and response to GEM after Hu R silencing were determined with the 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide test and the crystal violet clonogenic assay,respectively. To measure apoptosis,activation of caspases 3/7 was evaluated using immunofluorescence. RESULTS: In PDA tissue obtained from patients not treated with GEM,Hu R m RNA expression was 3.2 times lower(P < 0.05) and COX-2 and HO-1 m RNAexpression was 2.3-fold and 7.2-fold higher(P < 0.05),respectively,than normal pancreatic tissue(from organ donor). q RT-PCR analysis showed that Hu R,COX-2,and HO-1 m RNA were overexpressed in all cancer cell lines treated with the half maximal inhibitory concentration(IC50) dose of GEM compared with control cells(P < 0.05). Western blot analysis revealed that COX-2 and HO-1 levels were significantly decreased in cancer cells after Hu R silencing. Furthermore,HuR silencing in creased the response to GEM treatmentand decreased cell viability by 11.6%-53.7% compared to control cell lines. Caspases 3 and 7 were activated after Hu R silencing and GEM treatment in all pancreatic cancer cell lines. In comparison,treatment with GEM alone did not activate caspases 3 and 7 in the same cell lines. CONCLUSION: Hu R mediated post-transcriptional upregulation of COX-2 and HO-1 expression after GEM treatm展开更多
RNA结合蛋白HuR(human antigen R),又被称为类胚胎致死性异常视觉基因1(ELAV like RNA binding protein 1,ELAV1),是一种在机体各组织中广泛表达的重要RNA结合蛋白,其通过调控mRNA前体剪接、多聚腺苷酸化,以及mRNA稳定性与翻译效率等方...RNA结合蛋白HuR(human antigen R),又被称为类胚胎致死性异常视觉基因1(ELAV like RNA binding protein 1,ELAV1),是一种在机体各组织中广泛表达的重要RNA结合蛋白,其通过调控mRNA前体剪接、多聚腺苷酸化,以及mRNA稳定性与翻译效率等方式参与机体各项生命活动。研究表明,RNA结合蛋白参与了肌肉生长发育调控,其中HuR主要通过影响靶mRNAs的稳定性和翻译参与调控肌生成与肌肉疾病的发生。本文结合近年来HuR的相关研究,从HuR的生物学特性、主要功能与作用方式、在肌肉生长发育及肌肉疾病中的调控作用等方面展开综述,以期为进一步研究HuR在肌肉生长发育调控中的作用提供参考。展开更多
文摘Vascular endothelial growth factor （VEGF） is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization, translation, and differential cellular localization of various isoforms. Recent advances in our understanding of post-transcriptional regulation of VEGF include identification of the stabilizing mRNA binding protein, HuR, and the discovery of internal ribosomal entry sites in the 5＇UTR of the VEGF mRNA. Monoclonal anti-VEGF antibody was recently approved for use in humans, but suffers from the need for high systemic doses. RNA interference （RNAi） technology is being used in vitro and in animal models with promising results. Here, we review the literature on post-transcriptional regulation of VEGF and describe recent progress in targeting these mechanisms for therapeutic benefit.
文摘The RNA-binding proteins involved in regulation of mRNA post-transcriptional processing and translation control the fates of thousands of mRNA transcripts and basic cellular processes. The best studied of these, HuR, is well characterized as a mediator of mRNA stability and translation, and more recently, as a factor in nuclear functions such as pre-mRNA splicing. Due to HuR's role in regulating thousands of mRNA transcripts, including those for other RNA-binding proteins, HuR can act as a master regulator of cell survival and proliferation. HuR itself is subject to multiple post-translationa modifications including regulation of its nucleocytoplasmic distribution. However, the mechanisms that govern HuR levels in the cell have only recently begun to be defined. These mechanisms are critical to cell health, as it has become clear in recent years that aberrant expression of HuR can lead alternately to decreased cell viability or to promotion of pathological proliferation and invasiveness. HuR is expressed as alternate mRNAs that vary in their untranslated regions, leading to differences in transcript stability and translatability. Multiple transcription factors and modulators of mRNA stability that regulate HuR mRNA expression have been identified. In addition, translation of HuR is regulated by numerous microRNAs, several of which have been demonstrated to have anti-tumor properties due to their suppression of HuR expression. This review summarizes the current state of knowledge of the factors that regulate HuR expression, along with the circumstances under which these factors contribute to cancer and inflammation.
基金Supported by The European Social Fund under the Global Grant measure
文摘AIM: To investigate the expression of Hu R in pancreatic ductal adenocarcinoma(PDA) and to assess the effects of Hu R silencing on the expression of cyclooxygenase-2(COX-2) and heme oxygenase-1(HO-1) and the in vitro response to gemcitabine(GEM) treatment in pancreatic cell lines.METHODS: We compared the expression of Hu R,COX-2,and HO-1 in PDA and normal pancreatic tissueusing quantitative reverse transcription polymerase chain reaction(q RT-PCR) and western blot. In addition,the Hu R,COX-2 and HO-1 were analyzed in four types of cancer cell lines(Mia Paca2,Su.86.86,Capan-1,and Capan-2) with and without GEM treatment. Immunocytofluorescence analysis was used to investigate Hu R localization in cells. Cell viability and response to GEM after Hu R silencing were determined with the 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide test and the crystal violet clonogenic assay,respectively. To measure apoptosis,activation of caspases 3/7 was evaluated using immunofluorescence. RESULTS: In PDA tissue obtained from patients not treated with GEM,Hu R m RNA expression was 3.2 times lower(P < 0.05) and COX-2 and HO-1 m RNAexpression was 2.3-fold and 7.2-fold higher(P < 0.05),respectively,than normal pancreatic tissue(from organ donor). q RT-PCR analysis showed that Hu R,COX-2,and HO-1 m RNA were overexpressed in all cancer cell lines treated with the half maximal inhibitory concentration(IC50) dose of GEM compared with control cells(P < 0.05). Western blot analysis revealed that COX-2 and HO-1 levels were significantly decreased in cancer cells after Hu R silencing. Furthermore,HuR silencing in creased the response to GEM treatmentand decreased cell viability by 11.6%-53.7% compared to control cell lines. Caspases 3 and 7 were activated after Hu R silencing and GEM treatment in all pancreatic cancer cell lines. In comparison,treatment with GEM alone did not activate caspases 3 and 7 in the same cell lines. CONCLUSION: Hu R mediated post-transcriptional upregulation of COX-2 and HO-1 expression after GEM treatm
文摘RNA结合蛋白HuR(human antigen R),又被称为类胚胎致死性异常视觉基因1(ELAV like RNA binding protein 1,ELAV1),是一种在机体各组织中广泛表达的重要RNA结合蛋白,其通过调控mRNA前体剪接、多聚腺苷酸化,以及mRNA稳定性与翻译效率等方式参与机体各项生命活动。研究表明,RNA结合蛋白参与了肌肉生长发育调控,其中HuR主要通过影响靶mRNAs的稳定性和翻译参与调控肌生成与肌肉疾病的发生。本文结合近年来HuR的相关研究,从HuR的生物学特性、主要功能与作用方式、在肌肉生长发育及肌肉疾病中的调控作用等方面展开综述,以期为进一步研究HuR在肌肉生长发育调控中的作用提供参考。
