Dr Heike Laman
Research description
Ribbon diagrams of the FP domain of PI31 in two dimerization configurations: through the alpha helical domain (upper pair), and through the beta sheet interface (lower pair). Kirk, et al. J. Biol. Chem. 2008. 283(32):22325-35The D-type cyclin / Cyclin dependent kinase (Cdk) / INK4a / pRb regulatory pathway is frequently mutated in almost all types of cancers, including breast, brain, colon, lung and haematological malignancies. During early G1 phase of the cell cycle, when the cell is sensitive to mitogenic signals, D-type cyclins activate Cdks 4 and 6 to inactivate pRb and propel entry into S phase. My laboratory investigates the regulation of D-type cyclin/Cdk activity in order to understand how it impacts on the determination of cellular fates such as quiescence, proliferation, apoptosis, differentiation, or senescence. We are also investigating the deregulation of D-type cyclin/Cdk activity in human diseases, especially haematological malignancies and a Parkinsonian disease. We identified Fbxo7, a subunit of an SCF E3 ubiquitin ligase, as a novel regulator of D-type cyclin/Cdk6 complexes, specifically. Unusually, this F box protein acts as an assembly factor for D-type cyclin/Cdk6 complexes, suggesting that Fbxo7 itself has potential oncogenic activity. We are evaluating its functional effects in primary fibroblasts and haematopoietic stem cells. Mutations in Fbxo7 are also associated with Parkinsonian Pyramidal Syndrome, and we are characterising the inherited, recessive mutations in Fbxo7 that give rise to this early-onset neurodegenerative disease.
The major aim of our research is to understand how extracellular and intracellular signals impact on G1 cell cycle regulators to affect cellular decision making and ultimately cause human disease.