Functional Specialization of the Mediator-Associated Kinases CDK8 and CDK19

智力优势：现代生物学的一个主要挑战是阐明细胞在各种环境中调节数千个基因表达的分子机制。基因活性的精确调节是每个主要生物过程的关键要素。专门的蛋白质机器通过解码DNA中携带的信息来调节基因活性，以满足细胞不断变化的需求。一种这样的蛋白质复合物，称为介体，被认为是从酵母到人类的基因活性的关键调节因子，但对其作用机制知之甚少。该研究项目研究了介体复合物中两种蛋白质CDK8和CDK19的功能。初步结果表明，CDK8和CDK19调节参与不同细胞功能的不同基因组的活性。该项目旨在确定CDK8和CDK19使细胞能够调节不同基因组活性以响应细胞环境变化的分子机制。这项研究预计将有一个变革性的影响，特别是对调解人的理解和一般的基因表达控制机制的演变。鉴于Mediator在控制基因活性方面的准普遍作用，该项目的发现将在细胞和分子生物学领域产生深远的影响。此外，本项目开发的人类细胞中介体研究的创新技术，将在基因表达领域产生积极的涟漪效应，使其他基因调控因子的研究成为可能。更广泛的影响：本项目由大力促进科学教育和学术多样性的教学研究团队实施。这个协作小组包括本科生、研究生和博士后级别的受训人员，他们在一个显示性别平衡和包容少数群体的环境中工作。主办机构和主要研究者都积极参与旨在：a）增加少数民族学生获得博士学位的人数，B）为本科生提供实践研究经验，c）为本科生攻读生物科学博士学位做好准备，d）增加妇女在学术界领导职位中的代表性。这些努力的成功是由多个本科生作者在高影响力的出版物从这个实验室和事实，即在这个组中接受培训的30多名本科生中的大多数已经先进到研究生院，医学院或教学岗位记录。主要研究者是当地西班牙裔社区的活跃成员，也是博尔德科罗拉多大学公认的生命科学教育家，他是一门大型本科课程的讲师和几门研究生课程的共同讲师。该小组的成员通过定期向州和国家一级的大众媒体和外联活动投稿，促进公众的科学素养。

Intellectual Merit: A major challenge in modern biology is to elucidate the molecular mechanisms employed by cells to regulate expression of thousands of genes in various contexts. Accurate regulation of gene activity is a key element of every major biological process. Specialized protein machineries regulate gene activity by decoding the information carried in DNA to satisfy the ever-changing needs of the cell. One such protein complex, known as Mediator, is recognized as a critical regulator of gene activity from yeast to humans, yet little is known about its mechanism of action. This research project investigates the function of two proteins within the Mediator complex, CDK8 and CDK19. Preliminary results demonstrate that CDK8 and CDK19 regulate the activity of different groups of genes involved in diverse cellular functions. This project aims to define the molecular mechanisms by which CDK8 and CDK19 enable cells to adjust the activity of different gene sets in response to changes in the cellular environment. This research is expected to have a transformative impact on the understanding of Mediator in particular and the evolution of gene expression control mechanisms in general. Given the quasi-universal role of Mediator in the control of gene activity, the discoveries arising from this project will have far reaching implications in the fields of cellular and molecular biology. Moreover, the innovative techniques developed in this project for the study of Mediator in human cells will produce a positive ripple effect in the gene expression field by enabling similar studies of other gene regulators.Broader Impacts: This project is carried out by a teaching-research team that strongly promotes science education and diversity in academia. This collaborative team involves trainees at the undergraduate, graduate and post-doctoral levels who work in an environment displaying gender balance and inclusion of minorities. Both the host institution and the Principal Investigator participate actively in programs that aim to: a) increase the number of minority students earning PhDs, b) provide hands-on research experience to undergraduates, c) prepare undergraduate students to pursue PhDs in the biosciences, and d) increase the representation of women in leadership positions in academia. The success of these endeavors is documented by multiple undergraduate authors in the high impact publications from this laboratory and by the fact that most of the 30+ undergraduates trained in this group have advanced to graduate school, medical school or teaching positions. The Principal Investigator is an active member of the local Hispanic community and a recognized life science educator at the University of Colorado at Boulder, where he is the Instructor of a large undergraduate course and co-Instructor of several graduate courses. Members of this team promote scientific literacy in the public via regular contributions to the popular press and outreach activities at the state and national level.