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BACKGROUND A common event in the development of human neoplasia is the inactivation of a damage-inducible cell-cycle checkpoint pathway regulated by p53. One approach to the restoration of this pathway is to mimic the activity of key downstream effectors. The cyclin-dependent kinase (Cdk) inhibitor p21(WAF1) is one such molecule, as it is a major mediator(More)
We performed a systematic review of studies that investigated the effect of abnormalities of the tumour suppressor gene p53 upon prognosis in patients with colorectal cancer. The methods used to assess p53 status were immunohistochemistry (IHC), indicating abnormal accumulation of p53, and sequence analysis, indicating presence of p53 mutations (mut). We(More)
We have carried out a cell-based screen aimed at discovering small molecules that activate p53 and have the potential to decrease tumor growth. Here, we describe one of our hit compounds, tenovin-1, along with a more water-soluble analog, tenovin-6. Via a yeast genetic screen, biochemical assays, and target validation studies in mammalian cells, we show(More)
p53-Based cyclotherapy is proving to be a promising approach to palliate undesired effects of chemotherapy in patients with tumours carrying p53 mutations. For example, pre-treatment of cell cultures with Nutlin-3, a highly-selective inhibitor of the p53-mdm2 interaction, has been successfully used as a cytostatic agent to protect normal cells, but not(More)
BACKGROUND The CDKN2/INK4A tumour suppressor gene is deleted or mutated in a large number of human cancers. Overexpression of its product, p16, has been shown to block the transition through the G1/S phase of the cell cycle in a pRb-dependent fashion by inhibiting the cyclin D-dependent kinases cdk4 and cdk6. Reconstitution of p16 function in transformed(More)
The p53 tumour suppressor plays key regulatory roles in various fundamental biological processes, including development, ageing and cell differentiation. It is therefore known as " the guardian of the genome " and is currently the most extensively studied protein worldwide. Besides members of the biomedical community, who view p53 as a promising target for(More)
Side effects of chemotherapy are a major impediment in the treatment of cancer. Cyclotherapy is an emerging therapeutic strategy for protecting normal cells from the side effects of chemotherapy. Low, non-genotoxic doses of known p53 activators can be used to induce p53-dependent cell cycle arrest in normal cells bearing wild-type p53. This cytostatic(More)
Nutlin-3 selectively activates p53 by inhibiting the interaction of this tumor suppressor with its negative regulator murine double minute 2 (mdm2), while trichostatin A (TSA) is one of the most potent histone deacetylase (HDAC) inhibitors currently available. As both Nutlin-3 and TSA increase the levels of the cell cycle inhibitor p21(cip1/waf1) in cells,(More)
Commentary on: Apontes et al. " Exploring long-term protection of normal human fibroblasts and epithelial cells from chemo-therapy in cell culture " Oncotarget 2010; 2: 222-233. There is no novelty in stating that conventional cancer therapeutics are highly mutagenic, unselective and toxic. Hair loss, neutropenia, vomiting, and immune suppression are just(More)
Expression of the Epstein-Barr virus (EBV) latent membrane protein (LMP1) is regulated by virus- and host cell-specific factors. The EBV nuclear antigen 2 (EBNA2) has been shown to transactivate a number of viral and cellular gene promoters including the promoter for the LMP1 gene. EBNA2 is targeted to at least some of these promoters by interacting with a(More)