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Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro, but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer. Although they are(More)
In mice, the imprinted Igf2 gene (expressed from the paternal allele), which encodes a growth-promoting factor (IGF-II), is linked closely to the reciprocally imprinted H19 locus on chromosome 7. Also imprinted (expressed from the maternal allele) is the Igf2r gene on chromsome 17 encoding the type 2 IGF receptor that is involved in degradation of excess(More)
The cation-dependent and cation-independent mannose 6-phosphate receptors (CD- and CI-MPRs) bind the phosphomannosyl recognition marker of lysosomal hydrolases, but in mammals the latter also interacts with insulin-like growth factor II (IGF-II). While IGF signaling is mediated by the type 1 IGF receptor (IGF1R), the type 2 receptor (IGF2R/CI-MPR) serves(More)
Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 inhibits tumor formation. Nevertheless, it remains unclear whether they are the rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53(K117R)) or three (p53(3KR); K117R+K161R+K162R) of p53(More)
Mutations of the human BRCA1 and BRCA2 genes encoding tumor suppressors have been implicated in inherited predisposition to breast and other cancers. Disruption of the homologous mouse genes Brca1 and Brca2 by targeting showed that they both have indispensable roles during embryogenesis, because nullizygous embryos become developmentally retarded and(More)
The mammalian ortholog of the Drosophila MOF (males absent on the first) gene product is a histone H4 lysine 16-specific acetyltransferase. Recent studies have shown that depletion of human MOF (hMOF) in human cell lines leads to genomic instability, spontaneous chromosomal aberrations, cell cycle defects, altered nuclear morphology, reduced transcription(More)
In higher eukaryotes, the transport of soluble lysosomal enzymes involves the recognition of their mannose 6-phosphate signal by two receptors: the cation-independent mannose 6-phosphate/insulin-like growth factor II receptor (CI-MPR) and the cation-dependent mannose 6-phosphate receptor (CD-MPR). It is not known why these two different proteins are present(More)
Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, Brca1,53BP1(More)
Diabetes is a disorder characterized by loss of β cell mass and/or β cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell-derived β cells recapitulate molecular-physiological phenotypes of a diabetic subject, we generated induced pluripotent stem cells (iPSCs) from subjects with maturity-onset diabetes(More)
IGF-I and IGF-II are essential regulators of mammalian growth, development and metabolism, whose actions are modified by six high-affinity IGF binding proteins (IGFBPs). New lines of knockout (KO) mice lacking either IGFBP-3, -4, or -5 had no apparent deficiencies in growth or metabolism beyond a modest growth impairment (approximately 85-90% of wild type)(More)