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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 hyperactivated in glioma cell lines and tissue. (a) Cells from a range of human glioma cell lines were lysed and analysed from CREB expression and activation. All GBM cell lines tested showed an abundance of CREB protein, which was phosphorylated/activated. Non-tumour mouse brain tissue shows expression of CREB but no detectable pCREB. (b) Immunohistochemical analysis of human GBM tissue specimens show differential pCREB expression. (i) pCREB-positive tumour cells surround a tumour blood vessel; (ii) Giant cells in GBM show moderate-to-strong pCREB labelling; (iii) pseudopalidaing areas (arrows) in GBM show dense pCREB-positive tumour cells; (iv) and (v) two different patient tumours featuring oligodendroglial features show weak pCREB expression (arrows indicate oligodendroglial tumour cells); and (vi) double-labelling immunohistochemistry showed dense pCREB-positive cells (brown) surrounding foci with strong nestin expression (blue). (c) Brain tumour tissue microarray (US Biomax) with pCREB immunostaining. Top image shows the complete array with tumour grade layout indicated and cores magnified in the lower panel.
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fig1: CREB is hyperactivated in glioma cell lines and tissue. (a) Cells from a range of human glioma cell lines were lysed and analysed from CREB expression and activation. All GBM cell lines tested showed an abundance of CREB protein, which was phosphorylated/activated. Non-tumour mouse brain tissue shows expression of CREB but no detectable pCREB. (b) Immunohistochemical analysis of human GBM tissue specimens show differential pCREB expression. (i) pCREB-positive tumour cells surround a tumour blood vessel; (ii) Giant cells in GBM show moderate-to-strong pCREB labelling; (iii) pseudopalidaing areas (arrows) in GBM show dense pCREB-positive tumour cells; (iv) and (v) two different patient tumours featuring oligodendroglial features show weak pCREB expression (arrows indicate oligodendroglial tumour cells); and (vi) double-labelling immunohistochemistry showed dense pCREB-positive cells (brown) surrounding foci with strong nestin expression (blue). (c) Brain tumour tissue microarray (US Biomax) with pCREB immunostaining. Top image shows the complete array with tumour grade layout indicated and cores magnified in the lower panel.

Mentions: Although CREB is expressed throughout the normal brain during all stages of life, constitutively phosphorylated CREB (pCREB) is progressively restricted to neurogenic zones. It is within these zones that neural stem/progenitor cell (NSPC) populations reside and CREB gene/expression disruption studies in mice and zebrafish show that NSPC proliferation and survival depends on CREB function.21, 22 Based on data showing that CREB has oncogenic roles in the hemopoietic system12 and other tissues23 and as the CREB functions required by NSPCs may be important in GBM biology, we explored CREB expression, activation and function in brain tumour tissue and cells. Assessment of CREB expression and activation in human GBM tumour cell lines using CREB and pCREB antibodies revealed that GBM tumour lines showed robust CREB and pCREB expression. Non-tumour brain tissue exhibited weaker total CREB expression and undetectable levels of pCREB (Figure 1a).


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 hyperactivated in glioma cell lines and tissue. (a) Cells from a range of human glioma cell lines were lysed and analysed from CREB expression and activation. All GBM cell lines tested showed an abundance of CREB protein, which was phosphorylated/activated. Non-tumour mouse brain tissue shows expression of CREB but no detectable pCREB. (b) Immunohistochemical analysis of human GBM tissue specimens show differential pCREB expression. (i) pCREB-positive tumour cells surround a tumour blood vessel; (ii) Giant cells in GBM show moderate-to-strong pCREB labelling; (iii) pseudopalidaing areas (arrows) in GBM show dense pCREB-positive tumour cells; (iv) and (v) two different patient tumours featuring oligodendroglial features show weak pCREB expression (arrows indicate oligodendroglial tumour cells); and (vi) double-labelling immunohistochemistry showed dense pCREB-positive cells (brown) surrounding foci with strong nestin expression (blue). (c) Brain tumour tissue microarray (US Biomax) with pCREB immunostaining. Top image shows the complete array with tumour grade layout indicated and cores magnified in the lower panel.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: CREB is hyperactivated in glioma cell lines and tissue. (a) Cells from a range of human glioma cell lines were lysed and analysed from CREB expression and activation. All GBM cell lines tested showed an abundance of CREB protein, which was phosphorylated/activated. Non-tumour mouse brain tissue shows expression of CREB but no detectable pCREB. (b) Immunohistochemical analysis of human GBM tissue specimens show differential pCREB expression. (i) pCREB-positive tumour cells surround a tumour blood vessel; (ii) Giant cells in GBM show moderate-to-strong pCREB labelling; (iii) pseudopalidaing areas (arrows) in GBM show dense pCREB-positive tumour cells; (iv) and (v) two different patient tumours featuring oligodendroglial features show weak pCREB expression (arrows indicate oligodendroglial tumour cells); and (vi) double-labelling immunohistochemistry showed dense pCREB-positive cells (brown) surrounding foci with strong nestin expression (blue). (c) Brain tumour tissue microarray (US Biomax) with pCREB immunostaining. Top image shows the complete array with tumour grade layout indicated and cores magnified in the lower panel.
Mentions: Although CREB is expressed throughout the normal brain during all stages of life, constitutively phosphorylated CREB (pCREB) is progressively restricted to neurogenic zones. It is within these zones that neural stem/progenitor cell (NSPC) populations reside and CREB gene/expression disruption studies in mice and zebrafish show that NSPC proliferation and survival depends on CREB function.21, 22 Based on data showing that CREB has oncogenic roles in the hemopoietic system12 and other tissues23 and as the CREB functions required by NSPCs may be important in GBM biology, we explored CREB expression, activation and function in brain tumour tissue and cells. Assessment of CREB expression and activation in human GBM tumour cell lines using CREB and pCREB antibodies revealed that GBM tumour lines showed robust CREB and pCREB expression. Non-tumour brain tissue exhibited weaker total CREB expression and undetectable levels of pCREB (Figure 1a).

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