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, Rb1D326V/+, 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, Rb1D326V/+ 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.

An Artificial CTCF Peptide Triggers Efficient Therapeutic Efficacy in Ocular Melanoma

“… 21 , 22 In recent decades, researchers have concentrated on studying genetic lesions and have identified many gene targets that induce the development and metastasis of tumors. 23 , 24 , 25 Recently, increasing epigenetic lesions have been found to play an important role in tumorigenesis. 26 , 27 , 28 , 29 Abnormal chromosome conformation was especially recognized as a key factor in the tumorigenesis of several tumors.…”

Crocin inhibits proliferation and induces apoptosis through suppressing MYCN expression in retinoblastoma

“…As a malignant tumor, retinoblastoma arises from cone precursor cells or primitive retinal stem cells of the developing retina . The retinoblastoma protein, which encodes by the tumor suppressor RB1 gene, is a critical regulator of cellular replication through its binding to chromatin remodeling proteins and the E2F family . Mutation in both alleles of the retinoblastoma tumor suppressor gene RB1 is classically thought to be the main cause of the tumorigenesis in retinoblastoma .…”

Silencing circRNA protein kinase C iota (circ-PRKCI) suppresses cell progression and glycolysis of human papillary thyroid cancer through circ-PRKCI/miR-335/E2F3 ceRNA axis

“…tive potential [16], had been newly discovered to be targeted by miR-335. pRb/E2Fs was mutated in almost all human tumors [31], and E2F3 was required in the development and tumorigenesis of pRb-deficient thyroid tumors [32]. There were two distinct E2F3 proteins: E2F3a and E2F3b [16].…”