Mol Carcinog. 2010 January; 49(1): 94–103.
Colorectal cancer affects ~148,000 people/year in the United States and is the third most common cancer in men and women in this country [1]. Most colorectal cancers arise from adenomatous polyps, and the risk of developing colon polyps and cancer appears to be a result of the effect of genetic and environmental factors that promote the formation of adenomas and/or the progression of these adenomas to cancer [2]. These environmental and genetic factors contribute to colorectal cancer formation by promoting the accumulation of gene mutations and epigenetic alterations in colon epithelial cells that drive the polyp→cancer formation process.
Mol Carcinog. 2010 January; 49(1): 94–103.
Although aberrant DNA methylation has been recently shown to occur commonly in colorectal cancer, the causal role of these epigenetic changes in the process of cancer initiation and promotion is poorly understood at this time. It has been established that the aberrant hypermethylation of tumor suppressor genes can result in their transcriptional silencing, which is the mechanism through which DNA methylation is believed to promote cancer formation. DNA methylation appears to cooperate with concurrent alterations in chromatin structure to repress transcription [5–7]. However, little is known regarding the precise timing of these epigenetic alterations in the transition of normal colon epithelial cells to cancer cells through the polyp→cancer progression sequence. Furthermore, the biological role that these aberrantly methylated genes have on driving the formation of colorectal cancer is also poorly understood [8].
Mol Carcinog. 2010 January; 49(1): 94–103.
A well-established mouse model of colorectal cancer that has the potential to provide insight into the role of aberrant DNA methylation in the molecular pathogenesis of the polyp→cancer progression sequence is the azoxymethane (AOM) rodent colon cancer model. This model employs the carcinogen AOM to induce neoplasms that recapitulate the adenoma-carcinoma sequence in the mouse colon [9,10]. The AOM model also displays some of the common molecular events seen in human colorectal cancer, including the accumulation ofKrasmutations and increased COX2 expression [11–13]
Mol Carcinog. 2010 January; 49(1): 94–103.
Mouse models have already proven useful in studying the role of DNA methylation in the mouse skin multistage carcinogenesis [14]. Fragaet alassessed the role of DNA methylation in this well-characterized cancer model and found that specific epigenetic events correlated with both initiation steps and with progression steps. They identified several novel genes that were methylated in the mouse model and verified that they are also methylated in primary human cancers [14]. Aberrantly methylated genes have also been identified in mouse models of malignant fibrous histiocytomas, lung cancer, bladder cancer, and leukemia, demonstrating the potential to use mouse models to study the role of epigenetic alterations in cancer initiation and progression [15–19].Furthermore, with regards to mouse models of intestinal cancer and epigenetic alterations, recently, Hahn et al investigated the glutathione peroxidase Gpx1 and Gpx2 double knockout mouse using the genome wide methylation analytical technique MIRA (Methylated CpG island recovery assay) and identified a group of genes hypermethylated in chronically inflamed, aged, or neoplastic tissue, suggesting that mouse models of intestinal cancer likely display aberrant DNA hypermethylation [20]. It has also already been shown in both the AOM model and mutantApcmouse models of intestinal cancer that the global DNA hypomethylation observed in human colorectal malignancy is present in tumors arising in these mice suggesting the epigenetic alterations related to DNA methylation will be similar in these models to human colorectal cancer[21–23]. Furthermore, Linhart et al observed inApcmin/+mice over expressing DNA methyltransferase 3b1 (Dnmt3b1) that the mice develop larger, more frequent intestinal tumors compared to mice that express normal levels of Dnmt3b1[24]. In aggregate, these studies suggest that alterations in DNA methylation can contribute to tumor pathogenesis in mouse models. Consequently, we assessed the methylation state of tumor suppressor genes in the AOM colon cancer model to determine the role of epigenetic alterations in cancer initiation and progression.
Curr Opin Struct Biol
The vast majority of membrane protein complexes of biological interest cannot be purified to homogeneity, or removed from a physiologically relevant context without loss of function. It is therefore not possible to easily determine the 3D structures of these protein complexes using X-ray crystallography or conventional cryo-electron microscopy. Newly emerging methods that combine cryo-electron tomography with 3D image classification and averaging are, however, beginning to provide unique opportunities for in situ determination of the structures of membrane protein assemblies in intact cells and non-symmetric viruses. Here we review recent progress in this field and assess the potential of these methods to describe the conformation of membrane proteins in their in native environment.
STEM CELLS AND DEVELOPMENT
Dimethyloxaloylglycine (DMOG) is a cellpermeable prolyl-4-hydroxylase inhibitor, which can activate the expression ofHIF-1ain cells at normal oxygen tension.
STEM CELLS AND DEVELOPMENT
In previous studies, by activating the expression of HIF-1a, DMOG has been successfully used to attenuate postischemic myocardial injury and renal injury in remnant kidney, induce angiogenesis in ischemic skeletal muscles, and provide neuroprotection in a middle cerebral artery occlusion model.
