Normal proliferation and tumorigenesis but impaired pancreatic function in mice lacking the cell cycle regulator sei1

Abstract

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al. ; 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 beta-cell area, impaired insulin secretion, and glucose intolerance. These defects were associated to nuclear accumulation of the cell-cycle inhibitors p21(Cip1) and p27(Kip1) in islet cells. We conclude that Sei1 plays an important role in pancreatic beta-cells, which supports a functional link between Sei1 and the core cell cycle regulators specifically in the context of the pancreas. ; Work in the laboratory of M.S. is funded by the Centro Nacional de Investigaciones Oncológicas (CNIO) and by grants from the Spanish Ministry of Science (SAF and CONSOLIDER), the Regional Government of Madrid (GsSTEM), the European Union (PROTEOMAGE), the European Research Council (ERC), and the ''Marcelino Botin'' Foundation. Work in the laboratory of A.M.V. was funded by the Ministry of Science (BFU2008-02420) and by the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM). ; Peer reviewed