MOUSE MODELS FOR PRB GROWTH CONTROL VIA E2F/DP ACTION

Columbia Univ New York Morningside, New York NY

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Abstract

The retinoblastoma tumor suppressor (pRB) is a key cell cycle regulator that engages or disengages the cell cycle machinery in response to stimulatory or inhibitory signals for growth, survival and differentiation. Our broad long-term objective is to understand how pRB controls the normal processes of development, growth and differentiation in the whole animal, and how loss of pRB function results in these pathologies at the molecular level. Early models of tumor suppression predicted that pRB suppressed growth solely by binding and repressing free E2F/DP transcriptional activity that is normally required for cell cycle progression. However, the ever-growing list of pRB-interactors (>40) suggests that many proteins beside the E2F/DP transcription factors may serve as downstream effectors of pRB control. Thus, it will be critical to understand what subset of pRB-interactors actually are downstream effectors of pRB in vivo. To define the physiological function of E2F-1/DP-1 heterodimeric transcription factor and to determine whether it is a downstream effector of pRB action in vivo, we have created mutant mice which lack either E2F-1 or DP-1 by knock-out mouse technology. The radically distinct phenotypes of the E2F-1 or DP-1 mutant mice (tumors and tissue atrophy versus embryonic lethality) demonstrate that in vivo either half of the heterodimer has discrete temporal and spatial windows in which its function is critical in the whole animal. Further, we recently demonstrated that E2F-1 is a genuine downstream effector of pRB since loss of E2F-1 interferes with endocrine tumorigenesis induced by loss of pRB in Rb(+/-) x E2F-1 deficient animals. By understanding the mechanisms responsible for these tissue- specific and temporally distinct phenotypes, we will be positioned to control the development of these pathologies in the future. The following specific aims are proposed to understand how E2F/DP transcription factors act as molecular switches (gene activation versus repression) correctly interpreting and executing commands from pRB in the whole animals: (1) To understand how susceptible tissues degenerate or develop tumors in the E2F-1 deficient mice, (2) To determine how loss of DP-1 results in embryonic lethality, (3) To determine whether loss of E2F-1 interferes with the initiation or progression of endocrine tumors in Rb(+/-) mice and to determine how loss of E2F-1 lengthens lifespan of the Rb(+/-) animals.