Selective Requirements for E2f3 in the Development and Tumorigenicity of Rb-Deficient Chimeric Tissues

The tumor suppressor function of the retinoblastoma protein pRB is largely dependent upon its capacity to inhibit the E2F transcription factors and thereby cell proliferation. Attempts to study the interplay between pRB and the E2Fs have been hampered by the prenatal death ofRb ;E2f nullizygous mice. In this study, we isolatedRb ;E2f3 mutant embryonic stem cells and generatedRb − / − ;E2f3 − / − chimeric mice, thus bypassing the lethality of theRb − / − ;E2f3 − / − germ line mutant mice. We show that loss of E2F3 has opposing effects on two of the known developmental defects arising inRb − / − chimeras; it suppresses the formation of cataracts while aggravating the retinal dysplasia. This model system also allows us to assess howE2f3 status influences tumor formation inRb − / − tissues. We find thatE2f3 is dispensable for the development of pRB-deficient pituitary and thyroid tumors. In contrast,E2f3 inactivation completely suppresses the pulmonary neuroendocrine hyperplasia arising inRb − / − chimeric mice. This hyperproliferative state is thought to represent the preneoplastic lesion of small-cell lung carcinoma. Therefore, our observation highlights a potential role for E2F3 in the early stages of this tumor type.