Makelab
  • Research
Our longstanding interest is to characterize signaling pathways regulating mammalian cell growth and how these impinge on transcriptional responses in human disease

Signaling by the metabolic regulator and tumor supressor kinase LKB1

One of the rare kinases acting normally to restrict tumor growth is the LKB1serine/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 mesenchymal cells is required for suppression of epithelial hyperproliferation in a mouse polyposis model and likely also in the human Peutz-Jeghers syndrome. We are currently extending investigations of tumor suppression mechanisms of the LKB1 tumor 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 deletions) of LKB1 and LKB1 substrate mutations will be used with a specific interest in the Nuak2 and AMPK kinases and cytoskeletal regulation.   

Transcriptional regulation by cyclin-dependent kinases Cdk7 and Cdk8 in growth and differentiation

Two critical mediators of transcriptional responses involved in cancer and metabolism 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 identifying 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.

Actin cytoskeleton dynamics

Our recent work on LKB1 and another cytoskeleton-associated kinase Clik1 has triggered interest to identify regulators of the actin cytoskeleton in nonmuscle and in smooth muscle cells. As one approach new signaling components will be identified using a large-scale knockdown strategy combined with a cell-based high-content screening (HCS) system.

Publications