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Genetic instabilities in human cancers
There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
Requirement for p53 and p21 to sustain G2 arrest after DNA damage.
After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle. It is shown here that this arrest could be sustained only when p53 was present in the cell and…
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
This study uses a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits β-catenin-mediated transcription and reveals new mechanistic insights into the regulation of axin protein homeostasis, which presents new avenues for targeted Wnt pathway therapies.
Genetic instability in colorectal cancers
It is shown that colorectal tumours without microsatellite instability exhibit a striking defect in chromosome segregation, resulting in gains or losses in excess of 10 –2 per chromosome per generation, and that such instability can arise through two distinct pathways.
DNMT1 and DNMT3b cooperate to silence genes in human cancer cells
It is demonstrated that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and compelling evidence that such methylation is essential for optimal neoplastic proliferation is provided.
Mutations of mitotic checkpoint genes in human cancers
It is shown that CIN is consistently associated with the loss of function of a mitotic checkpoint in cancers displaying CIN, and in some cancersThe loss of this checkpoint wasassociated with the mutational inactivation of a human homologue of the yeast BUB1 gene; BUB 1 controls mitotic checkpoints and chromosome segregation in yeast.
Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status
- Harith Rajagopalan, A. Bardelli, C. Lengauer, K. Kinzler, B. Vogelstein, V. Velculescu
- 29 August 2002
The results not only provide genetic support for the idea that mutations in BRAF and KRAS exert equivalent effects in tumorigenesis, but also emphasize the role of repair processes in establishing the mutation spectra that underpin human cancer.
Genes expressed in human tumor endothelium.
It is demonstrated that tumor and normal endothelium are distinct at the molecular level, a finding that may have significant implications for the development of anti-angiogenic therapies.
Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells
Studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF genes, it is suggested that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors.
Disruption of p53 in human cancer cells alters the responses to therapeutic agents.
It was found that p53 had profound effects on drug responses, and these effects varied dramatically depending on the drug, having significant implications for future efforts to maximize therapeutic efficacy in patients with defined genetic alterations.