? Construction and inducible expression of dimer-specific mutants of AP-1 subunits in tissue culture cells.
? Generation and analysis of mice with altered AP-1 subunit abundance.
? Isolation of new, dimer-specific target genes.
? Functional analysis of target genes in cell transformation, apoptosis and cellular defense.
Physiologic and cancerous cell growth are determined by a balance of the regulatory processes that lead to either cell proliferation, differentiation or programmed cell death (apoptosis). The transcription factor AP-1, representing a homo- or heterodimer of members of the Jun, Fos and ATF proteins subfamilies address specific yet unknown target genes whose gene products are critically involved in all three phenotypes. There is solid evidence that each AP-1 transcription factor has very defined target promoters and target genes. Understanding the function of AP-1 subunits and the specific program of target genes will elucidate important facets of cancer mechanisms and most importantly help to define targets for anti-cancer drugs.
The goal of the project is to explore the properties and target genes of individual AP-1 dimers by decisively restricting their dimerization abilities by mutation. Specific AP-1 subunits that participate in the cancer process as well as in apoptosis and cell survival will be identified. Their link to upstream signaling pathways will be defined. Such knowledge will be the precondition to be able to manipulate their activities. From past experience it is already know that the role of a transcription factor and here specifically of a defined subunit combination, needs to be explored on both the cell culture level and in the intact organism. While the work in cell culture will yield such information as to which subunit combination is linked to which phenotype (cell cycle control, transformation, apoptosis, cell survival in response to genotoxic agents), and to what extent other regulatory proteins such as steroid/retinoid receptors determine the activity of this specific dimeric factor, a mouse with a dimerization-restricting mutation will clarify the role of this specific dimer in embryonic development and adult life and will also be important for attempts to modulate the activity in a tumour bearing organism.
apoptosis, AP-1, ATF, cell transformation, Fos, Jun, genotoxic agents, steroid/retinoid receptors, transcription factors
Funding SchemeCSC - Cost-sharing contracts
2300 AL Leiden