Abstract
Sei1 is a positive regulator of proliferation that promotes the assembly of Cdk4-cyclin D complexes and enhances the transcriptional activity of E2f1. The potential oncogenic role of Sei1 is further suggested by its overexpression in various types of human cancers. To study the role of Sei1, we have generated a mouse line deficient for this gene. Sei1-null fibroblasts did not show abnormalities regarding proliferation or susceptibility to neoplastic transformation, nor did we observe defects on Cdk4 complexes or E2f activity. Sei1-null mice were viable, did not present overt pathologies, had a normal lifespan, and had a normal susceptibility to spontaneous and chemically-induced cancer. Pancreatic insulin-producing cells are known to be particularly sensitive to Cdk4-cyclin D and E2f activities, and we have observed that Sei1 is highly expressed in pancreatic islets compared to other tissues. Interestingly, Sei1-null mice present lower number of islets, decreased β-cell area, impaired insulin secretion, and glucose intolerance. These defects were associated to nuclear accumulation of the cell-cycle inhibitors p21Cip1 and p27Kip1 in islet cells. We conclude that Sei1 plays an important role in pancreatic β-cells, which supports a functional link between Sei1 and the core cell cycle regulators specifically in the context of the pancreas.
Highlights
Entry from quiescence into the cell cycle and advance through G1 into S phase are controlled by the activity of the D-type cyclin-dependent kinases Cdk4 and Cdk6 (Cdk4,6/D complexes) [1]
Targeted embryonic stem (ES) clones were confirmed by Southern blot analysis (Fig. 1B) and were used to obtain Sei1-deficient mice
Complete Sei1 deficiency was corroborated by Northern blot analysis of Sei1-null ES cells (Fig. 1C) and qRT-PCR from Sei1-deficient Mouse embryo fibroblasts (MEFs) (Fig. 1D)
Summary
Entry from quiescence into the cell cycle and advance through G1 into S phase are controlled by the activity of the D-type cyclin-dependent kinases Cdk and Cdk (Cdk4,6/D complexes) [1]. Cdk4,6/D complexes phosphorylate members of the pocket protein family, namely, Rb, p107 and p130 These proteins bind and inhibit transcription factors important for cell cycle progression, most notably the E2f family of transcription factors, whose target genes are necessary for the replication of the DNA during S-phase. At a more physiological level, Cdk, D-type cyclins and the E2f family have a clear impact in pancreas development and homeostasis Mice deficient for these proteins display pancreatic abnormalities, mainly characterized by decreased numbers of b-cells which result in insulin resistance and diabetes [5,6,7]. Together, these observations indicate that b-cells are highly sensitive to the activity of the Cdk4/cyclinD/E2f pathway [8]
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