Abstract
During rat postnatal development, gastric cell proliferation and differentiation depend on many elements, which include dietary pattern, hormones, growth factors and their signaling pathways. Among them, EGFR activity is increased through MAPK and Src cascades in response to early weaning that represents the abrupt transition from milk to solid food. We herein investigated the direct involvement of ERK pathway in the control of cell cycle progression during early weaning, and studied the specific role of p27. At 15 days, Wistar rats were separated from dams, fed with powdered chow and daily injected with PD98059 (MEK inhibitor, 300 µg/kg) or 0.5% DMSO (control). By using HE staining and immunohistochemistry for PCNA, we respectively detected mitotic (MI) and proliferative (PI) indices in 18-day-old pups, and observed that both were reduced by PD98059. As cell cycle-related proteins (cyclin E, CDK2, cyclin D1, CDK4, p21 and p27) are involved in proliferative regulation, we compared samples obtained at 17 days in the morning (17 d) and evening (17.5 d). We found that they were not altered after ERK inhibition, but cyclin D1, p21 and p27 levels changed throughout the day in the control group. As p27 activity depends on its integrity, we studied p27 phosphorylation (threonin 187), and observed that ERK inhibition reduced this process. We suggest that MAPK pathway interferes in the regulation of p27 function in the gastric mucosa during early weaning, possibly by controlling its degradation, and altogether this mechanism might contribute to the increase of epithelial proliferation at this condition.
Highlights
Cell cycle progression is regulated by several proteins, and among them cyclins and cyclin-dependent kinases (CKDs) play important roles
Because ERK activation is increased in the gastric epithelium of early-weaned animals in parallel to stimulated cell proliferation, and MAPK signaling pathway is tightly related to cell cycle control, we investigated whether this cascade might be essential for early weaning effects
We studied the role of ERK activation in gastric epithelium cell proliferation during early weaning by using mitotic (MI) (Figure 2A–C) and proliferative indices (PI) (Figure 2D–G) which were determined in 18-day-old animals from control (Figure 2A, D) or PD98059-treated groups (Figure 2B,E)
Summary
Cell cycle progression is regulated by several proteins, and among them cyclins and cyclin-dependent kinases (CKDs) play important roles. CDK activity comprises the association with cyclin-dependent kinase inhibitory proteins (CKI) and phosphorylation events. Whereas INK4 proteins inhibit CDK4 and CDK6, Kip/Cip peptides are capable of binding a broad range of CDKs. p27Kip (p27) was first described as an inhibitor of cyclin E-CDK2 [5], it promotes the assembly and nuclear import of cyclin D-CDK4/6 [6,7], which contribute to cell cycle progression. In order to be targeted to destruction, cyclin ECDK2 complex phosphorylates p27 at threonin 187 (T187) [10], and phospho-p27 is ubiquitylated [11] by the F-box protein
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