Transactivator

Two domains, t1 and t2, exist which affect the GR post-DNA binding transcription activity (37). The major (t1) transactivation domain is 185 amino acid residues ia length with a 58-tesidue a-heUcal functional cote (38). The t1 domain is located at the N terminus of the proteia the minor (t2) trans activation domain residues on the carboxy-terminal side of the DNA binding domain. 

Transactivation. Protein synthesis is initiated or inhibited by the action of the activated GR on DNA. The use of glucocorticoids leads to antiinflammatory effects by first controlling gene expression, which subsequentiy leads to the synthesis and/or suppression of inflammation regulatory proteins. 

Although both the lOP- and the liP-group have been found to be important in connection with many GR antagonists, neither is a requirement for antiglucocorticoid activity. Cortexolone (15) acts as a GR antagonist in the tme sense of the term, blocking GR transactivation (127—129) although it does not include an liP-substituent. 

Figure 9.16 The polypeptide chain of the protein pS3 is divided into three domains with different functions transactivation, DNA binding and oligomerization.

The antiinflammatory effects of statins likely result from their ability to inhibit the formation of mevalonic acid. Downstream products of this molecule include not only the end product, cholesterol, but also several isoprenoid intermediates that covalently modify ( pre-nylate ) certain key intracellular signaling molecules. Statin treatment reduces leukocyte adhesion, accumulation of macrophages, MMPs, tissue factor, and other proinflammatory mediators. By acting on the MHC class II transactivator (CIITA), statins also interfere with antigen presentation and subsequent T-cell activation. Statin treatment can also limit platelet activation in some assays as well. All these results support the concept that in addition to their favorable effect on the lipid profile, statins can also exert an array of antiinflammatory and immunomodulatory actions. 

Alterations to the P53 gene are the most common genetic defects known in cancer [5]. The protein product of P53 is involved in a number of pathways that directly and indirectly lead to apoptosis. Many genes that are involved in apoptosis can be induced by this protein, which is a transcriptional transactivator. The emerging hypothesis is that p53 is a central node of a complex apoptotic network that may function differ ently in diver se cell types and tissues. For example, Bax, the prototype proapoptotic member of the Bcl2 family, can be transcriptionally induced by p53 in certain, but not all, cell types. Like p53, Bax can modulate the extent to which cells are sensitive to apoptosis caused by therapeutic agents. 

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,... 

N-terminal domain is the least conserved region and contains the transactivation domain AF-1. 

Prenzel N, Zwick E, Daub H et al (1999) EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402 884-888... 

Tat-transactivation Anti-hCyclinTl intrabodies tdTat Transdominant HIV Tat protein scFV to Tat Tar decoy HIV-1 Bahner et al. 1996 Bevec et al. 1996 Duan et al. 1994 Malim et al. 1989 Malim et al. 1988 Reddy et al. 1999... 

RRE decoy CD34+ bone marrow cells Traps Rev and thus inhibits transactivation of HIV-1 gene expression Kohn et al. 1999... 

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