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Selective CREB-dependent cyclin expression mediated by the PI3K and MAPK pathways supports glioma cell proliferation.

Daniel P, Filiz G, Brown DV, Hollande F, Gonzales M, D'Abaco G, Papalexis N, Phillips WA, Malaterre J, Ramsay RG, Mantamadiotis T - Oncogenesis (2014)

Bottom Line: CREB overexpression in transgenic animals imparts oncogenic properties on cells in various tissues, and aberrant CREB expression is associated with tumours.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

CREB is activated in dividing cells. T98G cells were analysed for the colocalization of pCREB(Ser 133) with markers of cell proliferation: (a) PCNA, (b) phospho-histone (pH3), nd (c) BrdU.
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fig2: CREB is activated in dividing cells. T98G cells were analysed for the colocalization of pCREB(Ser 133) with markers of cell proliferation: (a) PCNA, (b) phospho-histone (pH3), nd (c) BrdU.

Mentions: Using the GBM cell line T98G to examine CREB activation, we show that pCREB coincides with cells in cycle. Specifically, pCREB is present in cells undergoing S-phase of the cell cycle as shown by co-labelling with PCNA and newly divided cells labelled with the nucleotide analogue bromodeoxyuridine (BrdU; Figure 2). In contrast, cells labelled with the M-phase marker phospho-histone 3 (pH3) demonstrated poor colocalization to pCREB-positive cells.


Selective CREB-dependent cyclin expression mediated by the PI3K and MAPK pathways supports glioma cell proliferation.

Daniel P, Filiz G, Brown DV, Hollande F, Gonzales M, D'Abaco G, Papalexis N, Phillips WA, Malaterre J, Ramsay RG, Mantamadiotis T - Oncogenesis (2014)

CREB is activated in dividing cells. T98G cells were analysed for the colocalization of pCREB(Ser 133) with markers of cell proliferation: (a) PCNA, (b) phospho-histone (pH3), nd (c) BrdU.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150215&req=5

fig2: CREB is activated in dividing cells. T98G cells were analysed for the colocalization of pCREB(Ser 133) with markers of cell proliferation: (a) PCNA, (b) phospho-histone (pH3), nd (c) BrdU.
Mentions: Using the GBM cell line T98G to examine CREB activation, we show that pCREB coincides with cells in cycle. Specifically, pCREB is present in cells undergoing S-phase of the cell cycle as shown by co-labelling with PCNA and newly divided cells labelled with the nucleotide analogue bromodeoxyuridine (BrdU; Figure 2). In contrast, cells labelled with the M-phase marker phospho-histone 3 (pH3) demonstrated poor colocalization to pCREB-positive cells.

Bottom Line: CREB overexpression in transgenic animals imparts oncogenic properties on cells in various tissues, and aberrant CREB expression is associated with tumours.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.

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.

No MeSH data available.


Related in: MedlinePlus