Abstract
BackgroundThe transcription factor E2F4 controls proliferation of normal and cancerous intestinal epithelial cells. E2F4 localization in normal human intestinal epithelial cells (HIEC) is cell cycle-dependent, being cytoplasmic in quiescent differentiated cells but nuclear in proliferative cells. However, the intracellular signaling mechanisms regulating such E2F4 localization remain unknown.ResultsTreatment of quiescent HIEC with serum induced ERK1/2 activation, E2F4 phosphorylation, E2F4 nuclear translocation and G1/S phase transition while inhibition of MEK/ERK signaling by U0126 prevented these events. Stimulation of HIEC with epidermal growth factor (EGF) also led to the activation of ERK1/2 but, in contrast to serum or lysophosphatidic acid (LPA), EGF failed to induce E2F4 phosphorylation, E2F4 nuclear translocation and G1/S phase transition. Furthermore, Akt and GSK3β phosphorylation levels were markedly enhanced in serum- or LPA-stimulated HIEC but not by EGF. Importantly, E2F4 phosphorylation, E2F4 nuclear translocation and G1/S phase transition were all observed in response to EGF when GSK3 activity was concomitantly inhibited by SB216763. Finally, E2F4 was found to be overexpressed, phosphorylated and nuclear localized in epithelial cells from human colorectal adenomas exhibiting mutations in APC and KRAS or BRAF genes, known to deregulate GSK3/β-catenin and MEK/ERK signaling, respectively.ConclusionsThe present results indicate that MEK/ERK activation and GSK3 inhibition are both required for E2F4 phosphorylation as well as its nuclear translocation and S phase entry in HIEC. This finding suggests that dysregulated E2F4 nuclear localization may be an instigating event leading to hyperproliferation and hence, of tumor initiation and promotion in the colon and rectum.
Highlights
The transcription factor E2F4 controls proliferation of normal and cancerous intestinal epithelial cells
MEK/ERK pathway is required for E2F4 nuclear translocation and G1/S phase transition of HIEC We have previously shown that E2F4 is required for proper expression of many cell cycle regulatory proteins controlling G1/S phase transition and for proliferation of normal human intestinal epithelial cells (HIEC) [10]
In contrast to E2F1, which is constitutively localized in the nucleus, E2F4 has a diffuse cytoplasmic localization in quiescent HIEC and a nuclear localization in proliferative cells suggesting that its localization is regulated by signaling pathways activated by mitogens [9]
Summary
The transcription factor E2F4 controls proliferation of normal and cancerous intestinal epithelial cells. E2F4 localization in normal human intestinal epithelial cells (HIEC) is cell cycle-dependent, being cytoplasmic in quiescent differentiated cells but nuclear in proliferative cells. The first three family members, E2F1, 2 and 3a, are primarily considered as transcriptional activators. Their functions in hyperproliferation of basal keratinocytes and induces hyperplasia [6]. E2F4 is strongly and preferentially expressed in proliferative zones of embryonic mouse intestine [8] and human fetal intestinal epithelium [9]. Inhibition of E2F4 expression by RNA interference in normal and cancerous intestinal epithelial cells reveals that E2F4 is necessary for S-phase entry and proliferation [10]
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