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.

STAT3-mediated MMP-2 expression is required for 15-HETE-induced vascular adventitial fibroblast migration

“…CREB plays a major role in the regulation of cell migration and proliferation during development and disease processes [22,23]. In fact, CREB-mediated IL-6 expression was required for 15-HETE-induced VSMC migration and proliferation [4].…”

“…CREB regulates cell migration and proliferation [22,23]. To examine whether 15-HETE treatment activates CREB, we performed Western blot analysis using phosphor-specific antibodies.…”

Cyclin D1, cancer progression, and opportunities in cancer treatment

“…Cumulatively, this supports a model where PI3K is indispensable for EGF-induced cyclin D1 upregulation. In glioma cells, cyclic-AMP response element binding (CREB) protein acts as a critical hub that mediates PI3K-Akt-induced cyclin D1 upregulation upon mitogenic stimulation [25]. Modulation of cyclin D1 by the PI3K-Akt signaling pathway represents one mechanism of growth factor-dependent sensing by cyclin D1.…”

GPER1-mediated IGFBP-1 induction modulates IGF-1-dependent signaling in tamoxifen-treated breast cancer cells

“…Taken together, these results suggest that CREB activation downstream of GPER1 may play an inhibitory role in ERα-positive breast cancer cells. In contrast, CREB activation induces proliferation in tamoxifen-resistant breast cancer cells and other cancer cell types (Catalano et al, 2014; Daniel et al, 2014; Nguyen et al, 2014; Sofi et al, 2003). Furthermore, increased CREB expression in breast tumors is associated with poor prognosis, shorter survival and higher risk of metastasis (Chhabra et al, 2007; Fan et al, 2012).…”