Developmental defects and tumor predisposition in Rb mutant mice

Vooijs, Marc; Berns, Anton

doi:10.1038/sj.onc.1202999

Cited by 71 publications

(53 citation statements)

References 125 publications

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“…Two of these animals did develop tumors at 9 and 12 months of age. However, these were pituitary tumors, the typical tumor of Rb ϩ/Ϫ germ-line mutant and Rb Ϫ/Ϫ chimeric mutant animals (18). This result suggests that the Cre transgene is expressed at low levels in neuroendocrine tissues/ precursors.…”

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confidence: 79%

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Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage

Berman

Calo²,

Landman³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

247

267

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Mutation of the RB-1 and p53 tumor suppressors is associated with the development of human osteosarcoma. With the goal of generating a mouse model of this disease, we used conditional and transgenic mouse strains to inactivate Rb and/or p53 specifically in osteoblast precursors. The resulting Rb;p53 double mutant (DKO) animals are viable but develop early onset osteosarcomas with complete penetrance. These tumors display many of the characteristics of human osteosarcomas, including being highly metastatic. We established cell lines from the DKO osteosarcomas to further investigate their properties. These immortalized cell lines are highly proliferative and they retain their tumorigenic potential, as judged by their ability to form metastatic tumors in immunocompromised mice. Moreover, they can be induced to differentiate and, depending on the inductive signal, will adopt either the osteogenic or adipogenic fate. Consistent with this multipotency, a significant portion of these tumor cells express Sca-1, a marker that is typically associated with stem cells/uncommitted progenitors. By assaying sorted cells in transplant assays, we demonstrate that the tumorigenicity of the osteosarcoma cell lines correlates with the presence of the Sca-1 marker. Finally, we show that loss of Rb and p53 in Sca-1-positive mesenchymal stem/progenitor cells is sufficient to yield transformed cells that can initiate osteosarcoma formation in vivo.osx-cre ͉ Sca-1 ͉ hibernoma mouse model O steosarcomas account for Ϸ30% of malignant bone tumors and 3-4% of all childhood malignancies (1, 2). They arise primarily around the knee joint, lower femur and upper tibia, which are all regions of active bone growth and repair. These tumors are predominantly osteoblastic in nature, although there is a correlation between loss of differentiation and poor prognosis. The generation of new therapeutic treatments for osteosarcoma has improved the 5-year survival rate of affected individuals. However, like other mesenchymal neoplasms, osteosarcomas are predisposed to metastasize via the hematogenous route, and thus, pulmonary metastasis is a major cause of death. Analyses of both sporadic and hereditary tumors show that inactivation of the p53 and RB-1 tumor suppressors plays a key role in the development of this tumor type (1, 2). Li-Fraumeni patients, who often carry germ-line mutations in p53, are predisposed to a variety of tumors, 12% of which are bone sarcomas (3, 4). p53 mutations are also observed in 20-60% of sporadic osteosarcomas (5-7). Similarly, patients carrying germline mutations in RB-1 have an Ϸ500-fold higher incidence of osteosarcoma than the general population (8). Moreover, RB-1 mutations are detected in 70% of all adolescent osteosarcomas (9). Finally, human osteosarcomas can carry mutations in both p53 and RB-1 (10).Mouse models have provided considerable insight into the role of p53 in bone development and tumorigenesis. Experiments from three different settings suggest that p53 plays an important role in bone development by modul...

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confidence: 79%

“…Unfortunately, these conditional Rb mutant animals die at birth, precluding analysis of adult bone phenotypes. Heterozygous Rb mutant mice and Rb Ϫ/Ϫ /wild type chimeras are viable, but they develop pituitary and thyroid tumors, never osteosarcomas (18). Thus, to date, there is no mouse model of Rb mutant osteosarcoma.…”

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confidence: 99%

Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage

Berman

Calo²,

Landman³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

247

267

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“…Each serves as an essential positive regulatory subunit for the cyclindependent kinases Cdk-4 and Cdk-6, whereas the negative regulators associating with these kinases include the tumor suppressor p16. The essential target of Cdk-4 and Cdk-6 is the retinoblastoma tumor suppressor protein pRB, which guards a critical checkpoint to G1/S progression and is inactivated by hyperphosphorylation (Vooijs and Berns, 1999). Elimination of that normal checkpoint is now thought to be a general step in tumorigenesis, because the vast majority of tumors contain mutations that either remove pRB itself or promote its inactivation by augmenting Cdk-4 activity, usually by inducing cyclin D expression or eliminating p16 (Sherr, 1996).…”

Section: Cyclin D1mentioning

confidence: 99%

Transgenic models of lymphoid neoplasia and development of a pan-hematopoietic vector

et al. 1999

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The pathways to lymphoid neoplasia have been explored in a number of transgenic models. Because B lymphoid malignancies often involve translocation of an oncogene (e.g. myc, bcl-2, cyclin D1) to an immunoglobulin locus, resulting in its deregulated expression, the consequences of oncogene overexpression in lymphocytes can be evaluated with transgenes driven by an immunoglobulin regulatory element, such as an enhancer from the IgH locus. Mice bearing such transgenes have provided insight into the preneoplastic state, including alterations in the control of cellular proliferation, dierentiation or apoptosis. They have also allowed studies on oncogene cooperation in vivo and the modulating eect of genetic background. Brie¯y reviewed here are the models studied in the authors' laboratories. Mice bearing myc and bcl-2 transgenes have received most attention but others studied include abl, ras, cyclin D1 and bmi-1 oncogenes. Also discussed is a new transgenic vector that should facilitate transgenic approaches to non-lymphoid leukemias. The vector bears elements from the promoter region of the vav gene, which is expressed almost exclusively in hematopoietic cells. It has proven capable of driving transgene expression throughout the hematopoietic compartment, including progenitor cells and their precursors. This novel vector should aid studies on many aspects of hematopoiesis, including the modeling of leukemogenesis.

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“…In much of the developing mouse embryo, pRB loss does not have major effects on tissue pathology. In specific compartments, the genetic ablation of RB1 alters cell cycle progression/cell cycle exit, sensitivity to apoptosis, senescence, and differentiation (for review, see Vooijs and Berns 1999;Goodrich 2006;Viatour and Sage 2011;Sage 2012). The mutation of RB1 can alter the type of differentiation programs that are activated, the extent of differentiation that occurs, and the ability of differentiated cells to permanently exit the cell cycle (for examples, see Thomas et al 2001;Calo et al 2010; for review, see Thomas et al 2003;Sage 2012).…”

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confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

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Developmental defects and tumor predisposition in Rb mutant mice

Cited by 71 publications

References 125 publications

Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage

Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage

Transgenic models of lymphoid neoplasia and development of a pan-hematopoietic vector

RB1: a prototype tumor suppressor and an enigma

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