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 of Rb; E2f nullizygous mice. In this study, we isolated Rb; E2f3 mutant embryonic stem cells and generated Rb(-/-); E2f3(-/-) chimeric mice, thus bypassing the lethality of the Rb(-/-); E2f3(-/-) germ line mutant mice. We show that loss of E2F3 has opposing effects on two of the known developmental defects arising in Rb(-/-) chimeras; it suppresses the formation of cataracts while aggravating the retinal dysplasia. This model system also allows us to assess how E2f3 status influences tumor formation in Rb(-/-) tissues. We find that E2f3 is dispensable for the development of pRB-deficient pituitary and thyroid tumors. In contrast, E2f3 inactivation completely suppresses the pulmonary neuroendocrine hyperplasia arising in Rb(-/-) 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.
Parisi
Tiziana
T
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Yuan
Tina L
TL
Faust
Ann Marie
AM
Caron
Alicia M
AM
Bronson
Roderick
R
Lees
Jacqueline A
JA
D000818:Animals; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D050699:E2F3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D005123:Eye / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009928:Organ Specificity; D010900:Pituitary Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D050699:E2F3 Transcription Factor; D016160:Retinoblastoma Protein