Sei1 in Cancer and Diabetes Figure 8. Pancreatic islets in Sei1-null mice. (A) Levels of mRNA expression of the Sertad family members Sei1, Sertad2 and Sertad3, as well as, the pancreatic islet gene Kir6.2, were measured using qRT-PCR in total mRNA from isolated pancreatic islets of wt (n = 4) and Sei1-null (n = 2) male mice. (B–F) Paraffin sections of pancreas (n = 4 per genotype) of the indicated genotypes were stained with antibodies against insulin (B and C), p27Kip1 (D) or p21Cip1 (E). (B) Number of islets relative to the total area of the pancreas. (C) Ratio between the b-cell islet area and the total pancreas area. (D) p27Kip1- or (E) p21Cip1-positive nuclei relative to total b-cell area. (F) Representative examples of the indicated stainings. The dotted lines mark the limits of the pancreatic islets. Values correspond to the average and s.d. Statistical differences were determined by the Student’s t-test; *p,0.05; **p,0.01; and ***p,0.001. doi:10.1371/journal.pone.0008744.g008 Discussion Sei1 has been involved in the positive regulation of the cell cycle and proliferation [10,15–17] and, accordingly, its expression is upregulated in several types of tumors [16,18,25]. Experimental overexpression of Sei1 can provoke hyperproliferation [10], genomic instability [17] and inhibition of apoptosis [26]. In an effort to understand the role of Sei1 in the context of the organism, here we have generated and characterized Sei1 deficient mice. Experiments with primary fibroblasts and lymphocytes derived from Sei1-null mice did not reveal any cellular or molecular alteration regarding proliferation, immortalization, oncogenic transformation, and apoptotic responses to DNA damage. Furthermore, in the case of primary fibroblasts, Cdk4 complexes, Cdk2 activity, Rb phosphorylation, E2f transactivation and p53 responses were normal in the absence of Sei1. At the organismal level, Sei1-null mice were viable and showed no overt phenotypes, including normal lifespan, spontaneous tumors and chemically- induced tumors. The most probable explanation for this lack of phenotypes is redundancy with other members of the Sertad family that compensate for the absence of Sei1. Sertad2 is the closest relative to Sei1 and, indeed, Sei1 and Sertad2 share functional properties, including their ability to stimulate E2f1 activity [15]. Sei1 is also able to interact with Cdk4 and stimulate PLoS ONE | www.plosone.org 8 January 2010 | Volume 5 | Issue 1 | e8744