Transcriptional regulation of the cell cycle

Abstract

Transcriptional regulators play an important role during cell cycle progression. A subset of these even seems to have a critical function in regulating cell cycle transitions. In this thesis, I have addressed the importance of transcriptional control in the regulation of cell cycle progression, in particular at two critical transitions: the G0/G1 transition (cell cycle entry/exit) and the G2/M transition (coordination between DNA replication and segregation). In particular, my attention has focussed on the role of transcription factors of the Forkhead family in these transitions. In the first part of the thesis (chapters 1 to 3), the role of transcriptional regulation in cell cycle entry/exit was investigated. The background information on cell cycle entry/exit in the context of the immune compartment will be presented in Chapter 1, as T cells were used as experimental system in order to investigate this question. In particular, human primary T cells were used as they represent a particularly nice model for cell cycle entry of quiescent cells upon TCR stimulation. In addition, the mechanisms by which proliferation can be suppressed in inadequately proliferating T cells such as leukaemic T cells have been addressed in more detail. This can be achieved at different levels: by preventing T cell activation, by inducing a cell cycle arrest, or by inducing apoptosis. The cAMP-dependent pathway is known to suppress T cell proliferation and to induce tolerance in normal T cells. This is targeted by numerous drugs used in the clinic for immunosuppression or anti-cancer therapy. In Chapter 2, induction of cAMP-dependent signalling was examined as a way to suppress proliferation in leukaemic T cells. In Chapter 3, the role of FoxO Forkhead transcription factors in the regulation of cell cycle progression and apoptosis was studied in normal T cells. In particular, attention was focussed on their role during/after T cell activation. In the second part of this thesis (chapters 4 and 5), the role of another Forkhead transcription factor, FoxM1, in G2/M was investigated, and in particular, the regulation of FoxM1 transcriptional activity during the cell cycle. After reviewing the role of FoxM1 in cell cycle regulation and carcinogenesis in Chapter 4, the mechanisms of activation and inactivation of FoxM1 during cell cycle progression are discussed in Chapter 5. More specifically, the focus of the studies has been on the role of Cyclin A in FoxM1 activation during S/G2-phases and the mechanisms of inactivation of FoxM1 during mitotic exit. The observations made in these studies can explain the low levels of FoxM1 protein and activity during the G1-phase of the cell cycle. These mechanisms may involve FoxM1 dephosphorylation and degradation during mitotic exit. Finally, the main findings of these studies and their implications for further research will be summarized and discussed in Chapter 6.