Date Published: January 18, 2010
Publisher: Public Library of Science
Author(s): Pablo J. Fernandez-Marcos, Cristina Pantoja, Agueda Gonzalez-Rodriguez, Nicholas Martin, Juana M. Flores, Angela M. Valverde, Eiji Hara, Manuel Serrano, Kathrin Maedler. http://doi.org/10.1371/journal.pone.0008744
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.
Partial Text: In mammalian cells, 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) . The expression of D-type cyclins in response to extracellular mitogenic signals is tightly regulated at different levels, as well as their binding to Cdk4,6. An important level of regulation is exerted by the Cdk inhibitors (CKIs), which include the Ink4 family (p16Ink4a, p15Ink4b, p18Ink4c and p19Ink4d) and the Cip/Kip family (p21Cip1, p27Kip1 and p57Kip2) , . Once active, 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. Upon phosphorylation, the pocket proteins are released from the E2f transcription factors allowing them to become transcriptionally active . Alterations in the proteins that regulate the early stages of the cell cycle, including Cdk4, D-type cyclins and E2f1, have proven to be important in the development of cancer . At a more physiological level, Cdk4, 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 β-cells which result in insulin resistance and diabetes -. Together, these observations indicate that β-cells are highly sensitive to the activity of the Cdk4/cyclinD/E2f pathway .
Sei1 has been involved in the positive regulation of the cell cycle and proliferation , – and, accordingly, its expression is upregulated in several types of tumors , , . Experimental overexpression of Sei1 can provoke hyperproliferation , genomic instability  and inhibition of apoptosis . In an effort to understand the role of Sei1 in the context of the organism, here we have generated and characterized Sei1 deficient mice.