Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play ...Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.展开更多
We screened 95 kinase inhibitors whether they affect cAMP-dependent proteolysis of GATA-6 or not. Among them 7 inhibitors inhibited the proteolysis at the concentration range of μM around their IC50. They are inhibit...We screened 95 kinase inhibitors whether they affect cAMP-dependent proteolysis of GATA-6 or not. Among them 7 inhibitors inhibited the proteolysis at the concentration range of μM around their IC50. They are inhibitors for protein kinase A (H-89 and 4- cyano-3-methylisoquinoline), c-Jun N-terminal kinase (SP600125), phosphatidylinositol 3-kinase (Wort- mannin and LY-294002), casein kinase II (TBB) and cyclin dependent kinase (Cdk1/2 inhibitor III). It is of interest how these kinases play roles in the degradation process of GATA-6 since this transcription factor is essential for development and tissue-specific gene expression of mammals. Inhibitors identified in this study would be helpful to study molecular mechanisms of phenomena in which GATA-6 participates.展开更多
近年来在危重病监护方面有重大的进展,但是脓毒症仍有很高的发病率和死亡率[1],其本质是由于感染所致机体过度反应,引发炎症因子的过度分泌而引起的促、抗炎因子平衡失调。脂多糖(lipopolysaccharide,LPS)是引起脓毒症的重要因素之一,...近年来在危重病监护方面有重大的进展,但是脓毒症仍有很高的发病率和死亡率[1],其本质是由于感染所致机体过度反应,引发炎症因子的过度分泌而引起的促、抗炎因子平衡失调。脂多糖(lipopolysaccharide,LPS)是引起脓毒症的重要因素之一,它可以激活细胞内多条信号转导通路。丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号转导途径是体内重要的信号转导通路,参与调节胚胎发育、细胞分化、细胞增殖和细胞死亡,其中MAPK家族中的p38与炎症反应有着密切关系。本文着重综述p38的分子结构、p38信号转导通路的激活、p38的底物以及在由脂多糖激活的脓毒症中p38发挥的重要作用和应用p38抑制剂的防治前景。展开更多
Dysregulation of genes perpetuates cancer progression.During carcinogenesis,cancer cells acquire dependency of aberrant transcriptional programs(known as“transcription addiction”)to meet the high demands for uncontr...Dysregulation of genes perpetuates cancer progression.During carcinogenesis,cancer cells acquire dependency of aberrant transcriptional programs(known as“transcription addiction”)to meet the high demands for uncontrolled proliferation.The needs for particular transcription programs for cancer growth could be cancer-type-selective.The dependencies of certain transcription regulators could be exploited for therapeutic benefits.Anaplastic thyroid cancer(ATC)is an extremely aggressive human cancer for which new treatment modalities are urgently needed.Its resistance to conventional treatments and the lack of therapeutic options for improving survival might have been attributed to extensive genetic heterogeneity due to subsequent evolving genetic alterations and clonal selections during carcinogenesis.Despite this genetic complexity,mounting evidence has revealed a characteristic transcriptional addiction of ATC cells resulting in evolving diverse oncogenic signaling for cancer cell survival.The transcriptional addiction has presented a huge challenge for effective targeting as shown by the failure of previous targeted therapies.However,an emerging notion is that many different oncogenic signaling pathways activated by multiple upstream driver mutations might ultimately converge on the transcriptional responses,which would provide an opportunity to target transcriptional regulators for treatment of ATC.Here,we review the current understanding of how genetic alterations in cancer distorted the transcription program,leading to acquisition of transcriptional addiction.We also highlight recent findings from studies aiming to exploit the opportunity for targeting transcription regulators as potential therapeutics for ATC.展开更多
信号转导及转录激活因子3(signal transducers and activators of transcription 3,STAT3)是一种细胞内重要的转录因子,在体内可被其最常见的上游激酶JAK激酶(Janus kinase)磷酸化激活。众所周知,异常激活的STAT3促进肿瘤的发生发展,因...信号转导及转录激活因子3(signal transducers and activators of transcription 3,STAT3)是一种细胞内重要的转录因子,在体内可被其最常见的上游激酶JAK激酶(Janus kinase)磷酸化激活。众所周知,异常激活的STAT3促进肿瘤的发生发展,因此研究人员一直致力于研究一类靶向JAK/STAT3信号通路的抗肿瘤药物。笔者收集了近年来文献中报道的靶向JAK/STAT3信号通路的抑制剂研究及临床试验进展,对于部分抑制剂已经报道的靶点、作用机制和药效活性进行总结。展开更多
文摘Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.
文摘We screened 95 kinase inhibitors whether they affect cAMP-dependent proteolysis of GATA-6 or not. Among them 7 inhibitors inhibited the proteolysis at the concentration range of μM around their IC50. They are inhibitors for protein kinase A (H-89 and 4- cyano-3-methylisoquinoline), c-Jun N-terminal kinase (SP600125), phosphatidylinositol 3-kinase (Wort- mannin and LY-294002), casein kinase II (TBB) and cyclin dependent kinase (Cdk1/2 inhibitor III). It is of interest how these kinases play roles in the degradation process of GATA-6 since this transcription factor is essential for development and tissue-specific gene expression of mammals. Inhibitors identified in this study would be helpful to study molecular mechanisms of phenomena in which GATA-6 participates.
文摘近年来在危重病监护方面有重大的进展,但是脓毒症仍有很高的发病率和死亡率[1],其本质是由于感染所致机体过度反应,引发炎症因子的过度分泌而引起的促、抗炎因子平衡失调。脂多糖(lipopolysaccharide,LPS)是引起脓毒症的重要因素之一,它可以激活细胞内多条信号转导通路。丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号转导途径是体内重要的信号转导通路,参与调节胚胎发育、细胞分化、细胞增殖和细胞死亡,其中MAPK家族中的p38与炎症反应有着密切关系。本文着重综述p38的分子结构、p38信号转导通路的激活、p38的底物以及在由脂多糖激活的脓毒症中p38发挥的重要作用和应用p38抑制剂的防治前景。
基金supported by the Intramural Research Program of the Center for Cancer ResearchNational Cancer Institute,National Institutes of Health(ZIA BC 011191).
文摘Dysregulation of genes perpetuates cancer progression.During carcinogenesis,cancer cells acquire dependency of aberrant transcriptional programs(known as“transcription addiction”)to meet the high demands for uncontrolled proliferation.The needs for particular transcription programs for cancer growth could be cancer-type-selective.The dependencies of certain transcription regulators could be exploited for therapeutic benefits.Anaplastic thyroid cancer(ATC)is an extremely aggressive human cancer for which new treatment modalities are urgently needed.Its resistance to conventional treatments and the lack of therapeutic options for improving survival might have been attributed to extensive genetic heterogeneity due to subsequent evolving genetic alterations and clonal selections during carcinogenesis.Despite this genetic complexity,mounting evidence has revealed a characteristic transcriptional addiction of ATC cells resulting in evolving diverse oncogenic signaling for cancer cell survival.The transcriptional addiction has presented a huge challenge for effective targeting as shown by the failure of previous targeted therapies.However,an emerging notion is that many different oncogenic signaling pathways activated by multiple upstream driver mutations might ultimately converge on the transcriptional responses,which would provide an opportunity to target transcriptional regulators for treatment of ATC.Here,we review the current understanding of how genetic alterations in cancer distorted the transcription program,leading to acquisition of transcriptional addiction.We also highlight recent findings from studies aiming to exploit the opportunity for targeting transcription regulators as potential therapeutics for ATC.
文摘信号转导及转录激活因子3(signal transducers and activators of transcription 3,STAT3)是一种细胞内重要的转录因子,在体内可被其最常见的上游激酶JAK激酶(Janus kinase)磷酸化激活。众所周知,异常激活的STAT3促进肿瘤的发生发展,因此研究人员一直致力于研究一类靶向JAK/STAT3信号通路的抗肿瘤药物。笔者收集了近年来文献中报道的靶向JAK/STAT3信号通路的抑制剂研究及临床试验进展,对于部分抑制剂已经报道的靶点、作用机制和药效活性进行总结。
