Appropriately controlled gene expression is fundamental for normal growth and survival of all living organisms. In eukaryotes, the tran- scription of protein-coding mRNAs is dependent on RNA polymerase II （Pol II）. ...Appropriately controlled gene expression is fundamental for normal growth and survival of all living organisms. In eukaryotes, the tran- scription of protein-coding mRNAs is dependent on RNA polymerase II （Pol II）. The multi-subunit transcription cofactor Mediator complex is proposed to regulate most, if not all, of the Pol II-dependent transcription. Here we focus our discussion on two subunits of the Mediator complex, cyclin-dependent kinase 8 （CDK8） and its regulatory partner Cyclin C （CycC）, because they are either mutated or amplified in a variety of human cancers. CDK8 functions as an oncoprotein in melanoma and colorectal cancers, thus there are considerable interests in developing drugs specifically targeting the CDK8 kinase activity. However, to evaluate the feasibility of targeting CDK8 for cancer therapy and to understand how their dysregulation contributes to tumorigenesis, it is essential to elucidate the in vivo function and regulation of CDKS-CycC, which are still poorly understood in multi-cellular organisms. We summarize the evidence linking their dysregulation to various cancers and present our bioinformatics and computational analyses on the structure and evolution of CDK8. We also discuss the implications of these observations in tumorigenesis. Because most of the Mediator subunits, including CDK8 and CycC, are highly conserved during eukaryotic evolution, we expect that investigations using model organisms such as Drosophila will provide important insights into the function and regulation of CDK8 and CycC in different cellular and developmental contexts.展开更多
Cancer is considered one of the most lethal diseases responsible for causing deaths worldwide.Although there have been many breakthroughs in anticancer development,cancer remains the major cause of death globally.In t...Cancer is considered one of the most lethal diseases responsible for causing deaths worldwide.Although there have been many breakthroughs in anticancer development,cancer remains the major cause of death globally.In this regard,targeting cancer-causing enzymes is one of the efficient therapeutic strategies.Biological functions like cell cycle,transcription,metabolism,apoptosis,and other depend primarily on cyclin-dependent kinases(CDKs).These enzymes help in the replication of DNA in the normal cell cycle process,and deregulation in the functioning of any CDK can cause abnormal cell growth,which leads to cancer.This review is focused on anticancer drug discovery against cell cycle CDK enzyme using an in silico technique,i.e.,molecular docking studies.Molecular docking helps in deciphering the key interactions formed within the inhibitor and the respective enzyme.This concise study provides an overview of the most current in silico research advancements made in the field of anticancer drug discovery.The findings presented in the current review article can help in understanding the nature of inhibitor-target interactions and provide information on the structural and molecular prerequisites for the inhibition of cell cycle CDKs.展开更多
基金supported by a sub-award of the NIH LEQSF-INBRE grant(P20RR016456) to WXa grant from the American Heart Association(11SDG7590123) to JYJ
文摘Appropriately controlled gene expression is fundamental for normal growth and survival of all living organisms. In eukaryotes, the tran- scription of protein-coding mRNAs is dependent on RNA polymerase II （Pol II）. The multi-subunit transcription cofactor Mediator complex is proposed to regulate most, if not all, of the Pol II-dependent transcription. Here we focus our discussion on two subunits of the Mediator complex, cyclin-dependent kinase 8 （CDK8） and its regulatory partner Cyclin C （CycC）, because they are either mutated or amplified in a variety of human cancers. CDK8 functions as an oncoprotein in melanoma and colorectal cancers, thus there are considerable interests in developing drugs specifically targeting the CDK8 kinase activity. However, to evaluate the feasibility of targeting CDK8 for cancer therapy and to understand how their dysregulation contributes to tumorigenesis, it is essential to elucidate the in vivo function and regulation of CDKS-CycC, which are still poorly understood in multi-cellular organisms. We summarize the evidence linking their dysregulation to various cancers and present our bioinformatics and computational analyses on the structure and evolution of CDK8. We also discuss the implications of these observations in tumorigenesis. Because most of the Mediator subunits, including CDK8 and CycC, are highly conserved during eukaryotic evolution, we expect that investigations using model organisms such as Drosophila will provide important insights into the function and regulation of CDK8 and CycC in different cellular and developmental contexts.
文摘Cancer is considered one of the most lethal diseases responsible for causing deaths worldwide.Although there have been many breakthroughs in anticancer development,cancer remains the major cause of death globally.In this regard,targeting cancer-causing enzymes is one of the efficient therapeutic strategies.Biological functions like cell cycle,transcription,metabolism,apoptosis,and other depend primarily on cyclin-dependent kinases(CDKs).These enzymes help in the replication of DNA in the normal cell cycle process,and deregulation in the functioning of any CDK can cause abnormal cell growth,which leads to cancer.This review is focused on anticancer drug discovery against cell cycle CDK enzyme using an in silico technique,i.e.,molecular docking studies.Molecular docking helps in deciphering the key interactions formed within the inhibitor and the respective enzyme.This concise study provides an overview of the most current in silico research advancements made in the field of anticancer drug discovery.The findings presented in the current review article can help in understanding the nature of inhibitor-target interactions and provide information on the structural and molecular prerequisites for the inhibition of cell cycle CDKs.
