E2F3 Loss Has Opposing Effects on Different pRB-Deficient Tumors, Resulting in Suppression of Pituitary Tumors but Metastasis of Medullary Thyroid Carcinomas

Abstract

The E2F transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor. We have previously shown that E2F3 plays a critical role in mediating the mitogen-induced activation of E2F-responsive genes and contributes to both the inappropriate proliferation and the p53-dependent apoptosis that arise in pRB-deficient embryos. Here we show that E2F3 also has a significant effect on the phenotype of tumor-prone Rb^+/− mice. The absence of E2F3 results in a significant expansion in the life spans of these animals that correlates with a dramatic alteration in the tumor spectrum. E2F3 loss suppresses the development of the pituitary tumors that normally account for the death of Rb ^+/− mice. However, it also promotes the development of medullary thyroid carcinomas yielding metastases at a high frequency. This increased aggressiveness does not seem to result from any change in p53 levels or activity in these tumors. We show that, instead, E2F3 loss leads to an increase in the rate of tumor initiation. Finally, analysis of Rb ^+/−; E2f3 ^+/− mice shows that this tumor-suppressive function of E2F3 is dose dependent.

ACKNOWLEDGMENTS

We thank Alicia Caron for excellent technical support in the generation of histological sections and stainings. We are also extremely grateful for the gift of key reagents from Tyler Jacks (Rb mutant mice), David MacPherson (γ-irradiated fibroblasts), and Frances Connor (p53 ^−/− tumor specimen). We thank members of the Lees lab for comments on the manuscript.

This work was supported by stipends to U.Z. from the DFG zi/98 and MERCK/MIT and by a grant to J.A.L. from the NIH (PO1-CA42063).