title: Novel retinoblastoma mutation abrogating the interaction to E2F2/3, but not E2F1, led to selective suppression of thyroid tumors.
abstract: Mutant mouse models are indispensable tools for clarifying gene functions and elucidating the pathogenic mechanisms of human diseases. Here, we describe novel cancer models bearing point mutations in the retinoblastoma gene (Rb1) generated by N-ethyl-N-nitrosourea mutagenesis. Two mutations in splice sites reduced Rb1 expression and led to a tumor spectrum and incidence similar to those observed in the conventional Rb1 knockout mice. The missense mutant, Rb1(D326V/+) , developed pituitary tumors, but thyroid tumors were completely suppressed. Immunohistochemical analyses of thyroid tissue revealed that E2F1, but not E2F2/3, was selectively inactivated, indicating that the mutant Rb protein (pRb) suppressed thyroid tumors by inactivating E2F1. Interestingly, Rb1(D326V/+) mice developed pituitary tumors that originated from the intermediate lobe of the pituitary, despite selective inactivation of E2F1. Furthermore, in the anterior lobe of the pituitary, other E2F were also inactivated. These observations show that pRb mediates the inactivation of E2F function and its contribution to tumorigenesis is highly dependent on the cell type. Last, by using a reconstitution assay of synthesized proteins, we showed that the D326V missense pRb bound to E2F1 but failed to interact with E2F2/3. These results reveal the effect of the pRb N-terminal domain on E2F function and the impact of the protein on tumorigenesis. Thus, this mutant mouse model can be used to investigate human Rb family-bearing mutations at the N-terminal region.
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center, Tsukuba, Ibaraki, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Toki
authors.forename: Maki
authors.initials: M
authors.lastname: Inoue
authors.forename: Osamu
authors.initials: O
authors.lastname: Minowa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Motegi
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Saiki
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masuya
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Shiroishi
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yao
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
mesh_terms: D000818:Animals; D050687:E2F1 Transcription Factor / Q000502:physiology*; D050703:E2F2 Transcription Factor / Q000502:physiology*; D050699:E2F3 Transcription Factor / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D016160:Retinoblastoma Protein / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000209:etiology / Q000235:genetics*
chemical_list: D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D016160:Retinoblastoma Protein
keywords: E2F transcription factors; endocrine tumors; mice; mutagenesis; retinoblastoma
references.citation: Mol Cell Biol. 2003 Sep;23(18):6542-52
references.pmid: 12944480
references.citation: PLoS One. 2013;8(3):e58463
references.pmid: 23516486
references.citation: Nat Genet. 1998 Apr;18(4):360-4
references.pmid: 9537419
references.citation: Genes Dev. 1996 Dec 1;10(23):2960-70
references.pmid: 8956997
references.citation: Oncogene. 1995 Apr 20;10(8):1615-20
references.pmid: 7731716
references.citation: Mol Cell Biol. 2000 Aug;20(16):5797-807
references.pmid: 10913163
references.citation: J Biol Chem. 1995 Sep 22;270(38):22571-6
references.pmid: 7673249
references.citation: Genes Dev. 1996 Dec 1;10(23):2949-59
references.pmid: 8956996
references.citation: Mol Cell Biol. 1997 Dec;17(12):7342-52
references.pmid: 9372965
references.citation: Cancer Sci. 2013 Jul;104(7):937-44
references.pmid: 23551873
references.citation: Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12036-40
references.pmid: 9342358
references.citation: Nat Genet. 1994 Aug;7(4):480-4
references.pmid: 7951317
references.citation: Oncogene. 2014 Jan 30;33(5):556-66
references.pmid: 23353822
references.citation: Cell. 2005 Dec 16;123(6):1093-106
references.pmid: 16360038
references.citation: Proc Natl Acad Sci U S A. 1985 Oct;82(19):6619-21
references.pmid: 3863118
references.citation: Hum Genet. 1980;56(1):53-8
references.pmid: 7203480
references.citation: Mol Cell Biol. 2006 Feb;26(4):1527-37
references.pmid: 16449662
references.citation: Cancer Cell. 2002 Aug;2(2):103-12
references.pmid: 12204530
references.citation: Mol Cell Biol. 2002 May;22(9):3103-10
references.pmid: 11940667
references.citation: Nature. 1992 Sep 24;359(6393):295-300
references.pmid: 1406933
references.citation: Nat Rev Cancer. 2008 Sep;8(9):671-82
references.pmid: 18650841
references.citation: Mol Cell. 2014 Mar 20;53(6):993-1004
references.pmid: 24613344
references.citation: J Clin Invest. 2010 Dec;120(12):4478-92
references.pmid: 21099110
references.citation: Oncogene. 1994 Apr;9(4):1021-7
references.pmid: 8134105
references.citation: J Virol. 1997 Dec;71(12):9410-6
references.pmid: 9371601
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3890-5
references.pmid: 11904439
references.citation: Nat Rev Mol Cell Biol. 2013 May;14(5):297-306
references.pmid: 23594950
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):704-9
references.pmid: 21187395
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6914-8
references.pmid: 8346196
references.citation: J Biol Chem. 2010 May 21;285(21):16286-93
references.pmid: 20223825
references.citation: Cell. 1995 May 5;81(3):323-30
references.pmid: 7736585
references.citation: Hum Mol Genet. 1999;8(10):1955-63
references.pmid: 10469849
references.citation: Nat Rev Cancer. 2008 Sep;8(9):714-24
references.pmid: 19143056
references.citation: Genes Dev. 2000 Apr 1;14(7):804-16
references.pmid: 10766737
references.citation: Mol Vis. 2009;15:771-7
references.pmid: 19390654
references.citation: Mol Cell Biol. 1993 Oct;13(10):6501-8
references.pmid: 8413249
references.citation: Oncogene. 2004 Apr 22;23(19):3296-307
references.pmid: 15021915