Growth inhibition and DNA damage induced by Cre recombinase in mammalian cells

Loonstra, Ate; Vooijs, Marc; Beverloo, H. Berna; Allak, Bushra Al; Drunen, Ellen van; Kanaar, Roland; Berns, Anton; Jonkers, Jos

doi:10.1073/pnas.161269798

Cited by 539 publications

(517 citation statements)

References 40 publications

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“…In this context, oncogenic lesions that arise from stresses other than DSBs in Tp53 À/À cells before lymphocyte lineage commitment and/or in developing T lineage lymphocytes might drive thymocyte transformation more effectively than translocations that arise in B lineage cells. Although cre expression in cultured mouse embryonic cells causes genomic instability (Loonstra et al, 2001;Silver and Livingston, 2001), constitutive cre expression initiating in thymocytes neither leads to a detectable increase in genomic instability nor accelerates the development of thymic lymphomas in Tp53 À/À mice (Cheung et al, 2002). Still, it is possible that mb1-cre expression causes oncogenic translocations or other lesions that cooperate with RAG/AID-initiated translocations to accelerate the transformation of Tp53-deficient B lineage cells.…”

Section: Resultsmentioning

confidence: 99%

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

et al. 2011

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Inactivating Tp53 mutations are frequent genetic lesions in human tumors that harbor genomic instability, including B lineage lymphomas with IG translocations. Antigen receptor genes are assembled and modified in developing lymphocytes by RAG/AID-initiated genomic rearrangements that involve the induction of DNA double strand breaks (DSBs). Although TP53 inhibits the persistence of DSBs and induces apoptosis to protect cells from genomic instability and transformation, the development of spontaneous tumors harboring clonal translocations has not been reported in mice that only lack wild-type Tp53 protein or express Tp53 mutants. Tp53-deficient (Tp53 À/À ) mice succumb to T lineage lymphomas lacking clonal translocations but develop B lymphoid tumors containing immunoglobulin (Ig) translocations upon combined inactivation of DSB repair factors, RAG mutation or AID overexpression; mice expressing apoptosis-defective Tp53 mutants develop B cell lymphomas that have not been characterized for potential genomic instability. As somatic rather than germline inactivating mutations of TP53 are typically associated with human cancers and Tp53 deletion has cellular context dependent effects upon lymphocyte transformation, we generated mice with conditional Tp53 deletion in lineage-committed B lymphocytes to avoid complications associated with defective Tp53 responses during embryogenesis and/or in multilineage potential cells and, thereby, directly evaluate the potential physiological role of Tp53 in suppressing translocations in differentiated cells. These mb1-cre:Tp53 flox/flox mice succumbed to lymphoid tumors containing Ig gene rearrangements and immunophenotypes characteristic of B cells from various developmental stages. Most mb1-cre: Tp53 flox/flox tumors harbored clonal translocations, including Igh/c-myc or other oncogenic translocations generated by the aberrant repair of RAG/AID-generated DSBs.Our data indicate that Tp53 serves critical functions in B lineage lymphocytes to prevent transformation caused by translocations in cell populations experiencing physiological levels of RAG/AID-initiated DSB intermediates, and provide evidence that the somatic TP53 mutations found in diffuse large B-cell lymphoma and Burkitt's lymphoma may contribute to the development of these human malignancies.

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Section: Resultsmentioning

confidence: 99%

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

et al. 2011

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“…For abbreviations, see Table 1. pathologic condition further, however, it is possible that overexpression of Cre could be deleterious to neurons, as Cre expression has been shown to be toxic to cells in culture and in transgenic mice (Schmidt et al, 2000;Loonstra et al, 2001). Gene ablation by using the Cre-loxP system requires that Cre expression is spatially and temporally restricted to the tissue of interest, especially if one is studying the effects of ablating genes whose expression is widespread.…”

Section: Resultsmentioning

confidence: 99%

Characterization of transgene expression and Cre recombinase activity in a panel of Thy‐1 promoter‐Cre transgenic mice

Campsall¹,

Mazerolle²,

Repentingy³

et al. 2002

Developmental Dynamics

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The regulatory elements of the murine Thy1.2 gene were used to drive Cre recombinase expression in the nervous system (NS) of transgenic mice. Eleven Thy1-Cre lines exhibited transgene expression in several regions of the central and peripheral nervous systems, including the cerebral cortex, cerebellum, spinal cord, retina, and dorsal root ganglion. Thy1-Cre expression also resulted in region-specific activation of Cre reporter transgenes. Although Thy-1 expression is normally initiated in postmitotic neurons in the perinatal period, we show that the Thy-1.2 expression cassette drives Cre expression in immature proliferative zones in the NS as early as embryonic day 11 and in non-neural tissue. The Thy1.2 transgene cassette, therefore, does not impart transgene expression that is restricted to the NS or to postmitotic neurons within the NS. This panel of Thy1-Cre transgenic mice, however, will be useful reagents for the ablation of genes whose transcripts are spatially or temporally restricted in the developing NS.

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“…Similar toxicity issues do exist for the Cre-loxP system also. Loonstra et al 51 have shown that Cre recombinase expression in cultured mammalian cells may result in a markedly reduced proliferation and also numerous chromosomal aberrations and an increased number of sister chromatid exchanges. However, they also demonstrated that the toxicity is dependent on the level of Cre recombinase activity.…”

Section: Discussionmentioning

confidence: 99%

MicroPET imaging of Cre–loxP-mediated conditional activation of a herpes simplex virus type 1 thymidine kinase reporter gene

et al. 2004

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Growth inhibition and DNA damage induced by Cre recombinase in mammalian cells

Cited by 539 publications

References 40 publications

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

Characterization of transgene expression and Cre recombinase activity in a panel of Thy‐1 promoter‐Cre transgenic mice

MicroPET imaging of Cre–loxP-mediated conditional activation of a herpes simplex virus type 1 thymidine kinase reporter gene

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