LOSS OF E2F-1 REDUCES TUMORIGENESIS AND EXTENDS THE LIFE-SPAN OF RB1(+ -)MICE/

Mutation of the retinoblastoma tumour-suppressor gene (RB) leads to th e deregulation of many proteins and transcription factors that interac t with the retinoblastoma gene product (pRB), including members of the E2F transcription factor family(1,2). As pRB is known to repress E2F transcriptional activity and overexpression of E2F is sufficient for c ell cycle progression, it is thought that pRB suppresses growth in par t by repressing E2F-mediated transcription(3). Previously, we reported that loss of E2f1 in mice results in tissue-specific tumour induction and tissue atrophy(4), demonstrating that E2F-1 normally controls gro wth both positively and negatively in a tissue-specific fashion(4,5). To determine whether E2F-1 deregulation-as a result of loss of pRB-pro motes proliferation in vivo, we have tested whether loss of E2f1 inter feres with the pituitary and thyroid tumorigenesis that occurs in Rb1( +/-) mice(6-9). We have found that loss of E2f1 reduces the frequency of pituitary and thyroid tumours, and greatly lengthens the lifespan o f Rb1(+/-); E2f1(-/-) animals, demonstrating that E2F-1 is an importan t downstream target of pRB during tumorigenesis. Furthermore. loss of E2f1 reduces a previously reported strain-dependent difference in Rb1( +/-) lifespan(9,10), suggesting that E2f1 or an E2F-1-regulated gene a cts as a genetic modifier between the 129/Sv and C57BL/6 strains.