ARF-BP1 as a potential therapeutic target

In this review, we discuss the recent identification of ARF-BP1 (also known as Mule, UREB1, E3histone, LASU1, and HectH9). ARF-BP1, a HECT domain-containing E3 ubiquitin ligase, interacts with ARF and p53. Its ubiquitin ligase activity is inhibited by ARF. Inactivation of ARF-BP1 stabilised p53 and induced apoptosis. Notably, inactivation of ARF-BP1 also caused cell growth repression in p53-null cells and breast cancer cells with mutant p53. Thus, ARF-BP1 emerges as a novel therapeutic target against cancer regardless of p53 status

Resveratrol increases BRCA1 and BRCA2 mRNA expression in breast tumour cell lines

International audienceThe phytochemical resveratrol, found in grapes, berries and peanuts, has been found to possess cancer chemopreventive effects by inhibiting diverse cellular events associated with tumour initiation, promotion and progression. Resveratrol is also a phyto-oestrogen, binds to and activates oestrogen receptors that regulate the transcription of oestrogen-responsive target genes such as the breast cancer susceptibility genes BRCA1 and BRCA2. We investigated the effects of resveratrol on BRCA1 and BRCA2 expression in human breast cancer cell lines (MCF7, HBL 100 and MDA-MB 231) using quantitative real-time RT-PCR, and by perfusion chromatography of the proteins. All cell lines were treated with 30 microM resveratrol. The expressions of BRCA1 and BRCA2 mRNAs were increased although no change in the expression of the proteins were found. These data indicate that resveratrol at 30 micro M can increase expression of genes involved in the aggressiveness of human breast tumour cell lines

The pathology of familial breast cancer: The pathology of familial breast cancer How do the functions of BRCA1 and BRCA2 relate to breast tumour pathology?

Women with mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, have an increased risk of developing breast cancer. Both BRCA1 and BRCA2 are thought to be tumour suppressor genes since the wild type alleles of these genes are lost in tumours from heterozygous carriers. Several functions have been proposed for the proteins encoded by these genes which could explain their roles in tumour suppression. Both BRCA1 and BRCA2 have been suggested to have a role in transcriptional regulation and several potential BRCA1 target genes have been identified. The nature of these genes suggests that loss of BRCA1 could lead to inappropriate proliferation, consistent with the high mitotic grade of BRCA1-associated tumours. BRCA1 and BRCA2 have also been implicated in DNA repair and regulation of centrosome number. Loss of either of these functions would be expected to lead to chromosomal instability, which is observed in BRCA1 and BRCA2-associated tumours. Taken together, these studies give an insight into the pathogenesis of BRCA-associated tumours and will inform future therapeutic strategies

Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

Background: Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. So far, it has not been easy to identify the driver genes underlying gains and losses. A powerful approach to identify these driver genes could be a cross-species comparison of array comparative genomic hybridization (aCGH) data from cognate mouse and human tumors. Orthologous regions of mouse and human tumors that are commonly gained or lost might represent essential genomic regions selected for gain or loss during tumor development. Methods: To identify genomic regions that are associated with BRCA1- and BRCA2-mutated breast cancers we compared aCGH data from 130 mouse Brca1?/?;p53?/?, Brca2?/?;p53?/? and p53?/? mammary tumor groups with 103 human BRCA1-mutated, BRCA2-mutated and non-hereditary breast cancers. Results: Our genome-wide cross-species analysis yielded a complete collection of loci and genes that are commonly gained or lost in mouse and human breast cancer. Principal common CNAs were the well known MYCassociated gain and RB1/INTS6-associated loss that occurred in all mouse and human tumor groups, and the AURKA-associated gain occurred in BRCA2-related tumors from both species. However, there were also important differences between tumor profiles of both species, such as the prominent gain on chromosome 10 in mouse Brca2?/?;p53?/? tumors and the PIK3CA associated 3q gain in human BRCA1-mutated tumors, which occurred in tumors from one species but not in tumors from the other species. This disparity in recurrent aberrations in mouse and human tumors might be due to differences in tumor cell type or genomic organization between both species. Conclusions: The selection of the oncogenome during mouse and human breast tumor development is markedly different, apart from the MYC gain and RB1-associated loss. These differences should be kept in mind when using mouse models for preclinical studies.MediamaticsElectrical Engineering, Mathematics and Computer Scienc

Expression of arf tumor suppressor in spermatogonia facilitates meiotic progression in male germ cells

The mammalian Cdkn2a (Ink4a-Arf) locus encodes two tumor suppressor proteins (p16Ink4a and p19Arf) that respectively enforce the anti-proliferative functions of the retinoblastoma protein (Rb) and the p53 transcription factor in response to oncogenic stress. Although p19Arf is not normally detected in tissues of young adult mice, a notable exception occurs in the male germ line, where Arf is expressed in spermatogonia, but not in meiotic spermatocytes arising from them. Unlike other contexts in which the induction of Arf potently inhibits cell proliferation, expression of p19Arf in spermatogonia does not interfere with mitotic cell division. Instead, inactivation of Arf triggers germ cell-autonomous, p53-dependent apoptosis of primary spermatocytes in late meiotic prophase, resulting in reduced sperm production. Arf deficiency also causes premature, elevated, and persistent accumulation of the phosphorylated histone variant H2AX, reduces numbers of chromosome-associated complexes of Rad51 and Dmc1 recombinases during meiotic prophase, and yields incompletely synapsed autosomes during pachynema. Inactivation of Ink4a increases the fraction of spermatogonia in S-phase and restores sperm numbers in Ink4a-Arf doubly deficient mice but does not abrogate γ-H2AX accumulation in spermatocytes or p53-dependent apoptosis resulting from Arf inactivation. Thus, as opposed to its canonical role as a tumor suppressor in inducing p53-dependent senescence or apoptosis, Arf expression in spermatogonia instead initiates a salutary feed-forward program that prevents p53-dependent apoptosis, contributing to the survival of meiotic male germ cells

Current findings for recurring mutations in acute myeloid leukemia

The development of acute myeloid leukemia (AML) is a multistep process that requires at least two genetic abnormalities for the development of the disease. The identification of genetic mutations in AML has greatly advanced our understanding of leukemogenesis. Recently, the use of novel technologies, such as massively parallel DNA sequencing or high-resolution single-nucleotide polymorphism arrays, has allowed the identification of several novel recurrent gene mutations in AML. The aim of this review is to summarize the current findings for the identification of these gene mutations (Dnmt, TET2, IDH1/2, NPM1, ASXL1, etc.), most of which are frequently found in cytogenetically normal AML. The cooperative interactions of these molecular aberrations and their interactions with class I/II mutations are presented. The prognostic and predictive significances of these aberrations are also reviewed

GATA transcription factors and haematopoiesis in early Xenopus development

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