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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-dependent cell cycle factor expression signalling network in GBM tumour cells. CREB lies downstream of both the PI3K and MAPK pathways and modulates cell cycle factor expression. Cyclin D1 is completely dependent on CREB activity while cyclin B1 and PCNA appear to require activation of both CREB and non-CREB mechanisms. The width of the arrow indicates the relative strength of the signal. The broken arrows pointing from CREB to AKT indicates the putative CREB-dependent regulation of the PI3K pathway.
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fig7: CREB-dependent cell cycle factor expression signalling network in GBM tumour cells. CREB lies downstream of both the PI3K and MAPK pathways and modulates cell cycle factor expression. Cyclin D1 is completely dependent on CREB activity while cyclin B1 and PCNA appear to require activation of both CREB and non-CREB mechanisms. The width of the arrow indicates the relative strength of the signal. The broken arrows pointing from CREB to AKT indicates the putative CREB-dependent regulation of the PI3K pathway.

Mentions: Overall, this study shows that pCREB is a marker of glioma grade and that CREB activation in GBM cells appears to modulate GBM tumour cell proliferation through the integration of signals from PI3K and MAPK pathways (Figure 7). We also show that CREB acts as a master transcriptional regulator of cyclin D1 in GBM. This observation is consistent with the spectrum of tumour cell types where CREB has been shown to regulate cyclin D1 expression, including malignant T-cells60 gastric cancer cells,61 breast cancer cells,62 embryonic carcinoma cells63 and prostate cancer cells. Furthermore, we establish that CREB may be part of a complex signalling feedback loop modulating the expression of cell cycle factors. Given the roles CREB has in regulating GBM cell proliferation and the convergence of multiple redundant cancer signalling pathways upon CREB, the use of anti-tumour therapeutic approaches incorporating CREB inhibitors would be expected to provide more effective anti-tumour responses and may bypass the inherent redundancy and associated drug resistance that promote tumour cell proliferation.


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-dependent cell cycle factor expression signalling network in GBM tumour cells. CREB lies downstream of both the PI3K and MAPK pathways and modulates cell cycle factor expression. Cyclin D1 is completely dependent on CREB activity while cyclin B1 and PCNA appear to require activation of both CREB and non-CREB mechanisms. The width of the arrow indicates the relative strength of the signal. The broken arrows pointing from CREB to AKT indicates the putative CREB-dependent regulation of the PI3K pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: CREB-dependent cell cycle factor expression signalling network in GBM tumour cells. CREB lies downstream of both the PI3K and MAPK pathways and modulates cell cycle factor expression. Cyclin D1 is completely dependent on CREB activity while cyclin B1 and PCNA appear to require activation of both CREB and non-CREB mechanisms. The width of the arrow indicates the relative strength of the signal. The broken arrows pointing from CREB to AKT indicates the putative CREB-dependent regulation of the PI3K pathway.
Mentions: Overall, this study shows that pCREB is a marker of glioma grade and that CREB activation in GBM cells appears to modulate GBM tumour cell proliferation through the integration of signals from PI3K and MAPK pathways (Figure 7). We also show that CREB acts as a master transcriptional regulator of cyclin D1 in GBM. This observation is consistent with the spectrum of tumour cell types where CREB has been shown to regulate cyclin D1 expression, including malignant T-cells60 gastric cancer cells,61 breast cancer cells,62 embryonic carcinoma cells63 and prostate cancer cells. Furthermore, we establish that CREB may be part of a complex signalling feedback loop modulating the expression of cell cycle factors. Given the roles CREB has in regulating GBM cell proliferation and the convergence of multiple redundant cancer signalling pathways upon CREB, the use of anti-tumour therapeutic approaches incorporating CREB inhibitors would be expected to provide more effective anti-tumour responses and may bypass the inherent redundancy and associated drug resistance that promote tumour cell proliferation.

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