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CREB-dependent mechanisms regulating neural stem/progenitor cell proliferation and neurogenesis

Final Report Summary - NEUROGENCREB (CREB-dependent mechanisms regulating neural stem/progenitor cell proliferation and neurogenesis)

Gliomas are a type of aggressive brain tumour which exhibit complex cellular and genetic heterogeneity, limiting effective targeted therapy approaches. The survival of a patients diagnosed with high-grade glioma is in the order of 14 months, even with the full complement of therapy, including surgery, radiation and chemotherapy. Understanding the complexities of such tumours requires knowledge of the factors contributing to the development and progression of the tumour. Amongst the factors involved in initiating cellular changes whereby cells can evolve from a normal cell to a cancer cell are the transcription factors.

The cyclic-AMP response element binding protein (CREB) is a phospho-regulated transcription factor modulating the expression of numerous genes in nerve cells. CREB has many roles in neuronal activation which has consequences on higher order brain functions such as memory and drug addiction behaviours. Gene knockout experiments in mice have revealed CREB's importance in neuronal survival and its role in neurodegenerative diseases. Adding to CREB's array of neuronal-specific functions, recent studies show that it also has a role in neural stem progenitor cell (NSPC) survival, differentiation and proliferation. There is also accumulating evidence implicating CREB in cancer and well described cancer pathways, such as the PI3K pathway, where studies have shown that aberrant CREB expression is associated with tumours in patients and animal models and that CREB can impart oncogenic properties on cells, in vitro and in vivo. This brings together the relatively new discoveries that CREB is important for neural stem cell biology and tumour cell biology and that CREB may in fact be acting as a tumour factor by influencing tumour stem cell growth (Mantamadiotis et al., 2012).

Research supported through the Marie Curie International Reintegration Grants (IRG) has led to the discovery that CREB is hyperactivated in patient gliomas and that the level of activation follows the severity of pathology. In other words, CREB is most activated in the most aggressive and advanced tumours. This implies that CREB may be important in controlling brain tumour growth and survival. This discovery also shows that CREB may be a novel biomarker and possible novel drug target. The latter view that CREB may be a critical therapeutic target in combination with other drugs is gaining traction from our continuing work showing that CREB is in part activated via a well-established cancer promoting pathway called the PI3K pathway which is already the focus of therapeutic targeting.