Marco Herold-Projects

Marco Herold-Projects


Elucidating a role for the pro-survival Bcl-2 family member A1 in cancer

The pro-survival Bcl-2 family member A1 (the human counterpart is called BFL1) has been implicated in diverse cancers, including various leukaemias as well as lymphomas and melanoma. We have developed a conditional A1 knockout model and approaches to delete A1/BFL-1 in cell lines. We will use these tools to define the role of this pro-survival protein in the development and sustained growth of different cancers.  

Post-translational regulation of A1 in vivo

The pro-survival BCL-2 protein A1/BFL1 is subject to stringent post-translational regulation culminating in degradation by the ubiquitin dependent proteasomal pathway. In collaboration with Dr Ingolf Berberich from the University of Wuerzburg, Germany, we have recently identified an E3-Ligase, which is responsible for A1 ubiquitination. We have developed new models to study the impact of the loss of this A1 E3-Ligase within the whole organism. Furthermore we have recently started to exploit whole genome editing screening tools  to identify other/ additional components of A1’s destruction machinery. Once candidates are identified, we will use genome editing technologies to generate new models to study their impact on A1 stability in vivo

Regulation of the pro-apoptotic BH3-only protein BIM

The pro-apoptotic BH3-only BCL-2 family member BIM is a key regulator of the haematopoietic system. Surprisingly little is known about the regulation of this pro-apoptotic BCL-2 protein. In order to unravel critical regulatory mechanisms of Bim RNA transcription and stability, as well as BIM protein stability we are performing overexpression and CRISPR/Cas9 screening experiments. In pilot studies we have already identified several interesting candidate regulators of BIM pro-apoptotic activity that are currently being validated. Moreover, we are also investigating Bim mRNA and BIM protein regulation in human cancer derived lines when they are treated with diverse chemotherapeutic agents. The aim of these studies is to identify the signaling cascades that induce BIM’s pro-apoptotic activity with the ultimate goal to harness these processes to develop improved cancer therapies.

Identification of novel tumour suppressor genes and oncogenes by CRISPR/Cas9 library screens in vivo

p53 is the most important gene in human cancer, which is mutated in 50% of human cancers. However, little is known about its tumour suppressive function. In order to identify the critical tumour suppressive pathways induced by p53 we are performing whole genome CRISPR/Cas9 screens in vivo.