Diabetes and exocrine pancreatic insufficiency in E 2 F 1 / E 2 F 2 double-mutant mice

Introduction Normal cellular proliferation and differentiation require the transcriptional control of a large number of genes. Aberrant expression of a single transcriptional regulator may result in neoplasia or in altered tissue differentiation and development (1). E2F transcription factors, targets of retinoblastoma family members, regulate the expression of many genes implicated in cell growth and differentiation (2–4). E2F was first found to be important for the transcriptional activation of genes involved in G1/S progression and DNA replication (2–4). Recently, DNA microarray analyses have extended the list of potential E2F target genes to include DNA damage checkpoint and repair genes, factors involved in chromatin assembly/condensation, chromosome segregation, mitotic spindle checkpoint, apoptosis, differentiation, and development (5–8). The E2F family is composed of six members (E2F1–6) that heterodimerize with DP proteins to form a DNA-binding transcriptional activator (2). Although much has been learned about the biological properties of the E2F transcription factors, the precise roles of each individual member, as well as the level of redundancy among them, need to be resolved. Chromatin immunoprecipitation assays in cultured cells have not detected the selective association of individual E2F-DP complexes to a variety of known E2F-regulated promoters (9, 10), suggesting that there is little target specificity and much redundancy among the E2F family members. Conversely, analysis of mouse strains carrying targeted mutations for individual E2F genes have shown that loss of individual E2Fs can have distinct developmental and physiological consequences, implying the existence of specific target genes for each E2F. E2F1–/– mice display defective thymocyte apoptosis and impaired thymic negative selection, increased tumor susceptibility, exocrine gland dysplasia, and testicular atrophy (11–14). E2F2–/– mice exhibit increased proliferation of hematopoietic cells and frequently develop autoimmunity and tumors (15, 16). E2F3–/– mice exhibit a partially penetrant embryonic lethality, and the surviving animals die prematurely with signs typical of congestive heart failure (17). E2F4–/– mice are runts and show defective maturation of particular cell types (18, 19), and E2F5–/– mice develop nonobstructive hydrocephalus as newborns (20). Importantly, a recent DNA microarray-based study comparing gene expression in E2F1–/– and WT mice identified E2F1-specific target genes whose promoters were bound exclusively by E2F1 (21), thus implying target gene specificity and unique functions among the E2Fs. Remarkably, these promoters do not contain consensus E2F sites, suggesting that E2F1 is recruited to the promoter regions either by binding to a novel sequence element or by interaction with another DNA-binding protein. Studies of mice carrying two or more mutant E2F loci simultaneously have shown that the development of a variety of tissues is mainly dependent on the dosage of individual E2F members, but these studies have also provided support for the specificity model for certain E2F-dependent functions. In E2F1/E2F3-compound mutant mice, almost all of the developmental and age-related defects arising in the individual E2F1–/– or E2F3–/– mice were exacerbated by the mutation of the other E2F, suggesting that the Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice