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PMID: 12944480 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas.

Molecular and cellular biology ·Vol. 23 ·No. 18 ·2003-09-00 ·Pages 6542-52

Ziebold U, Lee EY, Bronson RT, Lees JA

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.

MeSH Terms
Animals Animals, Newborn Carcinoma, Medullary/etiology,pathology E2F3 Transcription Factor Female Fetal Viability/genetics Gene Dosage Heterozygote Longevity Male Mice Mice, Mutant Strains Mutation Neoplasm Metastasis/genetics Phenotype Pituitary Neoplasms/genetics,prevention & control Retinoblastoma Protein/deficiency,genetics Thyroid Neoplasms/etiology,pathology Transcription Factors/deficiency,genetics,metabolism Tumor Suppressor Protein p53
Chemicals
E2F3 Transcription Factor E2f3 protein, mouse Retinoblastoma Protein Transcription Factors Tumor Suppressor Protein p53
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Ziebold Ulrike
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Lee Eunice Y
Bronson Roderick T
Lees Jacqueline A
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.18.6542-6552.2003
Published
2003-09-00
Pages
6542-52
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC193688
Subset
IM
Grants
NCI NIH HHS · P01 CA042063 · United States
NCI NIH HHS · P01 CA 42063 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.18.6542-6552.2003 PMC Full Text View journal details
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