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Published on: January 21, 2012
Selective requirements for E2f3 in the development and tumorigenicity of Rb-deficient chimeric tissues
Tiziana Parisi1, Tina L Yuan, Ann Marie Faust
1Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
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.
Insights
The retinoblastoma protein (pRB) and E2F3
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- The tumor suppressor retinoblastoma protein (pRB) inhibits cell proliferation by binding to E2F transcription factors.
- Studying pRB and E2F interactions is challenging due to the embryonic lethality of mice lacking both Rb and E2f genes.
Purpose of the Study:
- To investigate the role of E2F3 in developmental defects and tumor formation in pRB-deficient mice.
- To establish a viable mouse model for studying Rb and E2f3 interactions.
Main Methods:
- Generated embryonic stem cells and chimeric mice lacking both Rb and E2f3.
- Analyzed developmental defects (cataracts, retinal dysplasia) and tumor development in Rb(-/-); E2f3(-/-) chimeric mice.
Main Results:
- Loss of E2F3 suppressed cataracts but worsened retinal dysplasia in Rb(-/-) chimeras.
- E2F3 was dispensable for pituitary and thyroid tumor development in pRB-deficient mice.
- E2F3 inactivation prevented pulmonary neuroendocrine hyperplasia, a precursor to small-cell lung carcinoma.
Conclusions:
- E2F3 plays opposing roles in different developmental defects associated with pRB loss.
- E2F3 is not essential for pituitary and thyroid tumor formation in Rb(-/-) mice.
- E2F3 inactivation suppresses a key preneoplastic lesion in small-cell lung carcinoma, suggesting a potential therapeutic target.
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