title: Selective CREB-dependent cyclin expression mediated by the PI3K and MAPK pathways supports glioma cell proliferation.
abstract: The cyclic-AMP response element binding (CREB) protein has been shown to have a pivotal role in cell survival and cell proliferation. Transgenic rodent models have revealed a role for CREB in higher-order brain functions, such as memory and drug addiction behaviors. CREB overexpression in transgenic animals imparts oncogenic properties on cells in various tissues, and aberrant CREB expression is associated with tumours. It is the central position of CREB, downstream from key developmental and growth signalling pathways, which gives CREB this ability to influence a spectrum of cellular activities, such as cell survival, growth and differentiation, in both normal and cancer cells. We show that CREB is highly expressed and constitutively activated in patient glioma tissue and that this activation closely correlates with tumour grade. The mechanism by which CREB regulates glioblastoma (GBM) tumour cell proliferation involves activities downstream from both the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways that then modulate the expression of three key cell cycle factors, cyclin B, D and proliferating cell nuclear antigen (PCNA). Cyclin D1 is highly CREB-dependent, whereas cyclin B1 and PCNA are co-regulated by both CREB-dependent and -independent mechanisms. The precise regulatory network involved appears to differ depending on the tumour-suppressor phosphatase and tensin homolog status of the GBM cells, which in turn allows CREB to regulate the activity of the PI3K itself. Given that CREB sits at the hub of key cancer cell signalling pathways, understanding the role of glioma-specific CREB function may lead to improved novel combinatorial anti-tumour therapies, which can complement existing PI3K-specific drugs undergoing early phase clinical trials.
authors: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors: P
authors: P
authors: Daniel
authors: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors: G
authors: G
authors: Filiz
authors: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors: D V
authors: DV
authors: Brown
authors: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors: F
authors: F
authors: Hollande
authors: 1] Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia [2] Department of Anatomical Pathology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors: M
authors: M
authors: Gonzales
authors: NICTA Victorian Research Laboratories, Centre for Neural Engineering, The University of Melbourne, Carlton, Australia.
authors: G
authors: G
authors: D'Abaco
authors: Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece.
authors: N
authors: N
authors: Papalexis
authors: 1] Surgical Oncology Research Laboratory, Peter MacCullum Cancer Centre, Melbourne, Victoria, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors: W A
authors: WA
authors: Phillips
authors: 1] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia [2] Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors: J
authors: J
authors: Malaterre
authors: 1] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia [2] Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors: R G
authors: RG
authors: Ramsay
authors: 1] Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia [2] Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece.
authors: T
authors: T
authors: Mantamadiotis