Genes repression

The importance of cross-talk in GR actions is indicated by the construction of a GR dimerisation-deficient mutant mouse in which GR is unable to dimerise and therefore bind to DNA, thus separating the DNA-binding (transactivation) and inflammatory gene repression (transrepression) activities of glucocorticoids. In these animals dexamethasone was able to inhibit AP-1- and NF-kB-mediated gene transcription,... 

Figure 8.2 Schematic representation of Fur-mediated gene repression. (From Andrews et al., 2003. Reproduced with permission from Blackwell Publishing Ltd.)...

Figure 3. The many ways to lose a HAT. Decreased amounts of functional CBP protein and subsequent CBP s loss of function has been observed in different contexts of neurological disorders and neuronal apoptosis. RTS (Rubinstein-Taybi Syndrome) results from a mutation on one cbp gene allele. In several cases of polyQ diseases, CBP can be sequestred by the mutated polyQ proteins, forming aggregates in the cytoplasm or the nucleus. CBP proteasomal degradation was also shown to be favored by polyQ proteins. CBP is a caspase-6 substrate in cerebellar granule neurons (CGN) deprived of potassium modeling caspase-dependent apoptosis. Finally, cbp gene repression has been observed in oxidative stress-induced death of a motomeuronal cell line. The mechanisms by which CBP levels are reduced in motomeurons of ALS mice is still unknown...

In addition to heterochromatic silencing, SUV39H1 H3 methyltransferase and HPl are involved in repression of euchromatic genes. The transcription factor E2F has a pivotal role in regulating the expression of S-phase-specific genes. Repression of these genes is through the retinoblastoma (Rb) protein which binds to E2F. 

Shi, X. et al. (2006) ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature, 442, 96-99. 

Lan, F. et al. (2007) Recognition of immethylated histone H3 lysine 4 links BHC80 to LSDl-mediated gene repression. Nature, 448, 718-722. 

A further significant mechanism of transcription control is the repression of gene expression (review Cowell, 1994 Johnson, 1995). There are two types of gene repression to be distinguished in eucaryotes. On the one hand the chromatin structure can cause an unspecific repression of gene expression (see 1.4.6). On the other hand, analogous to the specific transcriptional activators, there are specific repressors of transcription. Their effect, in contrast to that of vmspecific repressors, is sequence-dependent and thus suitable for selective repression (Fig. 1.40). DNA sequences that mediate repression of transcription factors are termed silencers. 

As well as induction of the synthesis of the apoprotein portion of cytochrome P-450, there is also induction of the synthesis of the heme portion. Clearly, it is also necessary to have an increased amount of heme if there is an increase in the amount of the enzyme apoprotein being synthesized. Thus, the rate-limiting step in heme synthesis, the enzyme 5-aminolaevulinate synthetase, is inducible by both phenobarbital and TCDD. This is the result of transcriptional activation of the gene, which codes for the S-aminolaevulinate synthetase. It may be that the decrease in the heme pool, which results from incorporation of heme into the newly synthesized apoprotein, leads to derepression of the gene and hence increased mRNA synthesis. The gene repression could be heme-mediated, or heme may modulate P-450 genes. 

In the SOS system, multiple unlinked genes repressed by a single repressor are induced simultaneously when DNA damage triggers RecA protein-facilitated autocatalytic proteolysis of the repressor. 

Ki SH, Cho IJ, Choi DW, Kim SG. 2005 Glucocorticoid receptor (GR)-associated SMRT binding to C/EBPbeta TAD and Nrf2 Neh4/5 Role of SMRT recruited to GR in GSTA2 gene repression. 2005. Mol Cell Biol 25 4150-4165. 

Albert PR, Lemonde S. 5-HT1A receptors, gene repression, and depression guilt by association. Neuroscientist 2004 10 575-593. 

Retinoids in Cancer Prevention and Treatment Since the discovery of vitamin A, the observation that the main effects of deficiency are hyperplasia and loss of differentiation of squamous epithelium has raised speculation that the vitamin may he associated with carcinogenesis. Either deficiency may be a risk factor for cancer or increased intake may be protective. Deficient animals develop more spontaneous tumors and are more sensitive to chemical carcinogens, whereas liver reserves of vitamin A are lower in patients with cancer than in controls. One of the genes repressed by retinoic acid is the myc-oncogene. 

Gene repression can also occnr by preventing other factors from binding to their regnlatory sites in responsive genes (100, 101). 

Figure 6.26. Gene Expression Analysis Using Microarrays. The expression levels of thousands of genes can he simultaneously analyzed using DNA microarrays (gene chips). Here, analysis of 1733 genes in 84 hreast tumor samples reveals that the tumors can he divided into distinct classes based on their gene expression patterns. Red corresponds to gene induction and green corresponds to gene repression. [Adapted from C. M. Perou et al, Nature 406(2000) 747.]...

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