Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2

Sharan, Shyam K.; Morimatsu, Masami; Albrecht, Urs; Lim, Dae–Sik; Regel, Eva; Dinh, Christopher; Sands, Arthur; Eichele, Gregor; Hasty, Paul; Bradley, Allan

doi:10.1038/386804a0

Cited by 996 publications

(795 citation statements)

References 37 publications

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“…The result from heterozygous mice should be interpreted with caution. For example, heterozygous mice for BRCA1 or BRCA2 gene did not manifest defects or an increased rate of tumorigenesis (Liu et al, 1996;Hakem et al, 1996;Sharan et al, 1997). In addition, the phenotype of a tumor suppressor gene loss in human may not be mimicked by the phenotype in mice.…”

Section: Resultsmentioning

confidence: 99%

Induction of apoptosis and G2/M cell cycle arrest by DCC

et al. 1999

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Section: Resultsmentioning

confidence: 99%

Induction of apoptosis and G2/M cell cycle arrest by DCC

et al. 1999

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“…Like BRCA1, BRCA2 also co-localizes with RAD51 (Sharan et al, 1997). BRCA2-null embryos are also hypersensitive to g-irradiation and exhibit early embryonic lethality, which is partially rescued by a p53 mutation (Ludwig et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

et al. 1998

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Germline mutations of the Brca1 gene are responsible for most cases of familial breast and ovarian cancers, but somatic mutations are rarely detected in sporadic events. Moreover, mouse embryos de®cient for Brca1 have been shown to die during early embryogenesis due to a proliferation defect. These ®ndings seem incompatible with the tumor suppress function assigned to this gene and raise questions about the mechanism by which Brca1 mutations cause tumorigenesis. We now directly demonstrate that BRCA1 is responsible for the integrity of the genome. Murine embryos carrying a Brca1 null mutation are developmentally retarded and hypersensitive to girradiation, suggesting a failure in DNA damage repair. This notion is supported by spectral karyotyping (SKY) of metaphase chromosomes, which display numerical and structural aberrations. However, massive chromosomal abnormalities are only observed when a p53 7/7 background is introduced. Thus, a p53 dependent cell cycle checkpoint arrests the mutant embryos and prevents the accumulation of damaged DNA. Brca1 7/7 ®broblasts are not viable, nor are Brca1 7/7 : p53 7/7 ®broblasts. However, proliferative foci arise from Brca1 7/7 : p53 7/7 cells, probably due to additional mutations that are a consequence of the accumulating DNA damage. We believe that the increased incidence of such additional mutations accounts for the mechanism of tumorigenesis associated with Brca1 mutations in humans.

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“…Metformin inhibits soft agar growth and in vivo tumor proliferation Numerous studies have shown that growth in soft agar is a very good model to study tumorigenicity and is closely associated with the transformed property of cells (Sharan et al, 1997;Bost et al, 1999). To determine whether metformin inhibits anchorage-independent growth, we performed a soft-agar colony formation assay in absence or presence of 1 and 5 mM metformin renewed daily.…”

Section: Metformin Does Not Induce Apoptosismentioning

confidence: 99%

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G 0 /G 1 . This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27 kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

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Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2

Cited by 996 publications

References 37 publications

Induction of apoptosis and G2/M cell cycle arrest by DCC

Induction of apoptosis and G2/M cell cycle arrest by DCC

A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

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