This research theme involves the hereditary cancer syndromes Multiple Endocrine Neoplasia type 1 (MEN1) and MEN 2, caused by germline mutations in the RET- and the menin-gene, respectively.
MEN2 Project
MEN2 is mainly characterized by medullary thyroid carcinoma (MTC) and is caused by activating germline mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase. For MEN2 we have generated a transgenic mouse model with an activating germline mutation in the RET proto-oncogene. These mice indeed develop the characteristic MEN2 tumor MTC, which originates from the calcitonin-producing C-cells in the thyroid gland (Acton, et al. 2000). Next, we have studied the involvement of other genes in MTC tumorigenesis, both in the mouse and in human MTCs. These data suggested possible involvement of p53 and the Wnt signalling pathway ((Gujral et al., 2008). These two pathways have been further investigated by means of cross-breeding of the RET transgenic mice with p53 knock-out mice or with APC(min) mice. In both cases, introduction of these inactivated tumor suppressor genes promoted the development of MTC in the RET transgenic mice, providing in vivo evidence for the role of these pathways in MTC tumorigenesis (Acton et al.). Next we crossed the RET transgenic mice with P18/p27 knock out mice. This promoted development of MTC (Van Veelen et al., 2008a), demonstrating the tumour suppressor action of these cell cycle regulators in MTC development in vivo, as previously suggested by in vitro experiments(Joshi et al., 2006). Inactivating p18 mutations were also detected and characterized in human MTCs (Van Veelen et al., 2008b).
MEN2 Group
The following people have been working on this project:
- Jo Höppener (project leader)
- Kees Lips (project leader, Division of Internal Medicine)
- Wendy van Veelen (Ph.D. student)
- Carola van Gasteren (technician)
MEN1 Project
The MEN1 research involves the role of the menin protein (encoded by the menin gene) in MEN1-specific tumorigenesis. Menin is predominantly present in the cell nucleus, and has been shown to interact with several proteins which are involved in transcription regulation. We want to investigate how the normal physiological function of menin is changed by the mutations occurring in MEN1 families and how this contributes to tumour development.
MEN1 Group
The following people have been working on this project:
- Kees Lips (project leader, Division of Internal Medicine)
- Marc Timmers (project leader, Dept. of Physiol. Chem)
- Jo Höppener
- Koen Dreijerink (Ph.D. student, AGIKO).
Key publications:
Acton DS et al., Oncogene 2000
Dreijerink KM et al., Cancer Research 2006
Dreijerink KM et al., Nat Clin Pract Endicrinol Metab 2006
Joshi et al., Oncogene 2007
Gujral et al., Cancer Research 2008
Van Veelen W et al., Cancer Research 2008 (a)
Van Veelen W et al., Int J Cancer 2008 (b)
update: 22-12-2008