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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  E 2 F 1, but not  E 2 F 2/3, was selectively inactivated, indicating that the mutant  R b protein (  pRb  ) suppressed thyroid tumors by inactivating  E 2 F 1. Interestingly , Rb1   D326V/+   mice developed pituitary tumors that originated from the intermediate lobe of the pituitary, despite selective inactivation of  E 2 F 1. Furthermore, in the anterior lobe of the pituitary, other  E 2 F  were also inactivated. These observations show that p R b mediates the inactivation of  E 2 F  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  D 326 V  missense p R b bound to  E 2 F 1 but failed to interact with  E 2 F 2/3. These results reveal the effect of the p R b  N ‐terminal domain on  E 2 F  function and the impact of the protein on tumorigenesis. Thus, this mutant mouse model can be used to investigate human  R b family‐bearing mutations at the  N ‐terminal region.

Novel retinoblastoma mutation abrogating the interaction to E 2 F 2/3, but not E 2 F 1, led to selective suppression of thyroid tumors