@ Epigenetic regulation
1, DNA methylation: C to MC
CpG island methylation
eg, promoter hypermethylation of tumor suppressor gene silencing--- tumorigenesis
看一段文章: "To regulate the level at which any gene is expressed, there are complex sets of regulatory proteins that bind to parts of the DNA encoding each gene. In very complex organisms such as ourselves, many control factors have to be acting together to achieve the levels of power and refinement of gene regulation needed. One of these levels of control is provided by adding a small "tag" called a methyl group onto C, one of the bases that make up the DNA code. The methyl group tagged C's can be written as mC. Simpler organisms, such as many types of bacteria and the single-celled yeast, usually do not use methyl group tagged C's in regulating their genes. Some bacteria, but not all, use methyl group tagged A's (mA) for this purpose. "
另一段敘述: Origin of CpG (CG) islands
The CG island is a short stretch of DNA in which the frequency of the CG sequence is higher than other regions. It is also called the CpG island, where "p" simply indicates that "C" and "G" are connected by a phosphodiester bond.
CpG islands are often located around the promoters of housekeeping genes (which are essential for general cell functions) or other genes frequently expressed in a cell. At these locations, the CG sequence is not methylated. By contrast, the CG sequences in inactive genes are usually methylated to suppress their expression. The methylated cytosine may be converted to thymine by accidental deamination. Unlike the cytosine to uracil mutation which is efficiently repaired, the cytosine to thymine mutation can be corrected only by the mismatch repair which is very inefficient. Hence, over evolutionary time scales, the methylated CG sequence will be converted to the TG sequence. This explains the deficiency of the CG sequence in inactive genes.
Inheritance of the DNA methylation pattern
Any type of cells have their own methylation pattern so that a unique set of proteins may be expressed to perform functions specific for this cell type. Thus, during cell division, the methylation pattern should also pass over to the daughter cell. This is achieved by a specific enzyme called the maintenance methylase which can methylate only the CG sequence paired with methylated CG.
2, de novo -- adv. ( 副詞 adverb ) means= 重新,再次
3, histone modification
@ Cell signaling and human cancer
The development of cancer in rodents requires two genetic lesions, described by Knudson as the "two-hit hypothesis".
(1) One of those lesions eliminates p53 function, by mutation of p53 itself, loss of p19Arf, or overexpression of mdm2 (a p53-specific ubiquitin ligase). Elimination of p53 function frees those cancer cells from replicative senescence that otherwise limits the outgrowth of any given tumor.
(2) A second lesion activates a proliferative signal, and can be fulfilled by many genes, most of which are potential targets for intervention. Of note is that human cancer requires a third lesion, that is activation of telomerase. The first class of proliferative signals for cancer development is represented by growth factors and their receptors. Growth factor receptors are typically transmembrane proteins with tyrosine kinase activity intrinsic to, or associated with, their cytoplasmic tails. Intervention targeting growth factor receptors can take the form of antibodies that block receptor activation and potentially recruit immune responses to cancer cells overexpressing those receptors, or small molecule inhibitors of the associated tyrosine kinase activity. Herceptin was the first such product to reach the clinic, targeting cells overexpressing HER-2. The EGF receptor is a target present on most solid tumors, and is being targeted both with antibodies and small mol-ecules. As other receptors are linked to specific tumors with further research, new cancer targets will be identified and targeted with similar approaches. Activation of tyrosine kinases initiates a cascade of events that activates pathways leading to proliferation and resistance to apoptosis. The proliferative pathways involve Ras, which is also mutationally acti-vated in many human cancers, while the anti-apoptotic pathways involve PI 3-kinase. The down-regulator of PI 3-kinase is PTEN, a tumor suppressor often mutated in cancers. The effectors of Ras and PI 3-kinase include many protein kinases. Ras effectors include Raf, MEK, MAP kinase, Rsk, while the primary effector of PI 3-kinase is Akt, which directly phosphorylates many proapoptotic substrates, neutralizing their activity. All of those kinases present potential targets for small molecule inhibitors, and some are in various stages of development.
The most significant end-targets of these signaling pathways are the nuclear proteins and chromatin that regulate gene expression in the cell. Transcription factors are phosphorylated by protein kinases, resulting in their activation. Additionally, kinases are able to directly phosphorylate histones, initiating a series of events that lead to remodeling of chromatin in that region. For example, phosphorylation of Histone H3 on serine 10 by Rsk2, itself induced by EGF receptor activation, stimulates the activity of histone acetyl transferases that acetylate lysine 14 on the same histone molecule. By mechanisms not fully understood, this leads to acetylation of other lysine residues on other histones, and transcriptional activation of specific target genes. By contrast, methylation of lysines results in transcriptional repression. Already relevance to cancer is emerging, as the p21 Cip/WAF tumor suppressor is often shut off in cancer cells, and treatment with inhibitors of histone deacetylases (leading to increased acetylation) reactivates it, differentiating the tumor cells. Other histones are modified in conjunction with different biological outcomes. Histone H2A.X is phosphorylated stranded DNA breaks by anti-cancer agents, or early during apoptosis. As our understanding of the biology associated with histone modification is still emergent, it is likely many additional links to cancer will be discovered. Cell signaling pathways are integral to the regulation of cell function, and cancer is the dysregulation of cell proliferation, which is why the science of cell signaling is intertwined with cancer research, and increasingly, cancer treatment.
@ APC (macrophage, dendritic cell)-- IL-12 --- CD4+; CD8+
Th1: IL-2, IFN-r, TNF-b
Th2: IL-4,5,6,9,10, 13
IL-4 / IL-13-- B cell-- IgE--mast cell--- preformed granule (5mins, histamine, heparin)/ newly generated(-30mins: Prostaglandin etc; hrs: cytokine, TNF)
IL-4 / IL-13 -- smooth muscle-- Eotaxin
@ antiallergic properties: (1) IL-10 (2) Tr(regulatory T cells): CD4+/CD25+