Tomi Mäkelä

Director, Helsinki Institute of Life Science HiLIFE

Vice Director, Academy of Finland Center of Excellence in Translational Genome-Scale Biology

Kinase signaling linking metabolism and growth control

Major human diseases such as diabetes and cancer are due to deregulat- ed signaling stemming from genetic alterations and extrinsic factors. Signaling in pathways and in larger networks typically involves sequential activation of kinases phosphorylating substrates and thus relaying and amplifying signals ultimately mod- ulating transcriptional responses in target gene sets. Our longstanding interest is to characterize signaling pathways regulating mammalian cell growth and how these impinge on transcriptional responses in human disease.

tabolism are the transcriptional kinases Cdk7 and Cdk8 mediating signals to RNA polymerase II. We are investigating the molecular mechanisms and in vivo functions of Cdk7 and Cdlk8 combining mouse molecular genetics with Drosophila knockdown strategies and cell-based screening approaches. Recent discoveries include identify- ing that Cdk7 acts as a roadblock to adipogenesis and that this presumed ubiquitous basal transcription factor is not expressed in fat tissues. Our goal is to understand the basis for the specificity of transcriptional regulation by metazoan Cdk7 and Cdk8 and their contribution to growth control and differentiation.

One of the rare kinases acting normally to restrict tumor growth is the LKB1ser- ine/threonine kinase critical for activation of at least 14 related kinases involved in metabolism and polarity regulation. We are interested in how LKB1 mediates its tumor suppressing function, and recently identified that LKB1 signaling in mesen- chymal cells is required for suppression of epithelial hyperproliferation in a mouse polyposis model and likely also in the human Peutz-Jeghers syndrome. We are cur- rently extending investigations of tumor suppression mechanisms of the LKB1 tu- mor suppressor kinase from hereditary polyposis to sporadic cancer (lung, uterine cervix). For this a combination of tissue- and cell type specific targeting approaches in vivo (conditional mouse models) and in vitro (2D and 3D RNAi & conditional dele- tions) of LKB1 and LKB1 substrate mutations will be used with a specific interest in the Nuak2 and AMPK kinases and cytoskeletal regulation.