Functional Specialization of the Mediator-Associated Kinases CDK8 and CDK19

智力价值：现代生物学的一个主要挑战是阐明细胞在不同环境中调节数千个基因表达的分子机制。对基因活性的准确调控是每一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动，以满足细胞不断变化的需求。其中一种被称为Mediator的蛋白质复合体被认为是从酵母到人类的基因活性的关键调节因子，但人们对其作用机制知之甚少。本研究项目研究了CDK8和CDK19这两种蛋白在介体复合体中的功能。初步结果表明，CDK8和CDK19调节参与不同细胞功能的不同组基因的活性。该项目旨在确定CDK8和CDK19使细胞能够调节不同基因组的活性以应对细胞环境变化的分子机制。这项研究有望对特别是对介体的理解以及基因表达调控机制的总体进化产生革命性的影响。鉴于介体在基因活性控制中的准普遍作用，该项目的发现将对细胞和分子生物学领域产生深远的影响。此外，该项目为研究人类细胞中的介体而开发的创新技术，将通过使其他基因调控因子的类似研究成为可能，在基因表达领域产生积极的涟漪效应。广泛影响：该项目由一个大力推动科学教育和学术界多样性的教研团队实施。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。主办机构和首席研究人员都积极参与旨在：a)增加获得博士学位的少数族裔学生的数量，b)为本科生提供实践研究经验，c)使本科生为攻读生物科学博士做好准备，以及d)增加女性在学术界担任领导职务的比例。这些努力的成功被多个本科生作者记录在这个实验室的高影响力出版物上，以及在这个群体中接受培训的30多名本科生中大多数已经晋升到研究生院、医学院或教师职位的事实。首席调查员是当地西班牙裔社区的活跃成员，也是科罗拉多大学博尔德分校公认的生命科学教育家，在那里他是一个大型本科生课程的讲师和几个研究生课程的联合讲师。该小组的成员通过定期向大众媒体捐款以及在州和国家一级开展外联活动，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.