A transcription factors

One such hypotheses submits that most antidepressants enhance the expression of cyclo-AMP response element binding protein (CREB), which is a transcription factor that after phosphorylation binds to cyclo-AMP response elements localized in the promoter region of many genes including that coding for brain... 

CREB stands for cyclic-AMP response element (CRE) binding protein and is a transcription factor. When phosphorylated by cyclic AMP- and cyclic GMP-dependent Protein Kinases or other protein kinases it binds to gene promoters that contain a specific binding site. After binding, the respective transcription activity is modulated. 

Cytokines. Figure 1 Inhibition of cytokine synthesis during activation of the specific immune system. The monoclonal antibodies Muromonab and Basiliximab are specific for the CD3 complex of the T-cell receptor, and for the IL-2 receptor on lymphocytes, respectively. Cyclosporin and Tacrolimus inhibit activation of cytoplasmic NF-AT, a transcription factor essential for activation of the IL-2 gene ( NFAT Family of Transcription Factors). Sirolimus interferes with mTOR signaling and inhibits IL-2 dependent proliferation. Red pharmaka, blue target proteins. 

PPARy is a transcription factor which controls the expression of enzymes and proteins involved in fat and glucose metabolism. More importantly, stimulation of this receptor induces differentiation of preadipocytes to adipose cells. It is believed that the formation of additional, small fat cells lowers free fatty acids and hepatic triglycerides, thereby collecting insulin resistance. 

NF-IL6 is a nuclear factor for interleukin-6, a transcription factor which is activated by IL-6 and other cytokines and stimulates stress protein gene expression. 

Activation of transcription by the binding of a transcription factor to a DNA-regulatory sequence. 

Nuclear factor-KB Nuclear factor-kappa B (NF-kB) is a transcription factor that regulates cytokine production. 

The immediate early gene product c-Fos (cellular feline osteosarcoma) has widely been used as a useful marker of neuronal activation. Fos, the protein encoded by the c-fos gene, is a transcription factor that triggers transcription in a cascade of cellular responses. To determine which neuron groups are involved in the response to PGD2 and/or adenosine, especially A2aR agonists, we examined Fos-immunoreactivity under these conditions (Scammell et al., 1998, 2001 Satoh et al., 1999). 

Finally, the third level of molecular description can be illustrated by the complex formed between a transcription factor and the DNA molecule. In such a complex, the atoms involved in the interaction, the hydrogen bonds formed between the amino acids and the bases are shown, because this description, is necessary to explain the specificity of molecular recognition. 

Fig. 3.13. A simplified version of a genetic construct which requires not only a reading frame to generate the m-RNA and then the protein but requires a binding region for the polymerase machinery and an instruction region for the binding of a transcription factor, both of which must be bound in appropriate form before reading can occur. The form of the transcription factor which may interact by feedback with an element, M, can be adjusted (by [M]) to stop reading. The whole is necessary for cell operations not just for that of DNA reactions.

Fig. 20.6 Regulation of bcl-2 levels by chronic lithium and VPA the role of MAP kinases and GSK-3. This figure depicts a mechanism by which lithium and VPA may regulate bcl-2 levels. Both lithium and VPA are known to regulate MAP kinases and GSK-3/i, both of which should result in increases in AP-1 DNA-bind-ing activity. PEBP2j6 is known to be regulated by AP-1 sites, and, thus, lithium and VPA produce an increase in PEBP2/ transcript and protein levels, and ultimately in the function of PEBP2/ . PEBP2/ serves as a transcription factor in concert with PEBP2a and regulates...

Cyclic AMP controls phosphorylation of the cAMP response element binding protein. Activation of a transcription factor known as the cAMP response element... 

This same strategy can be attempted at the mRNA level to inhibit the translation of individual mRNAs. These experiments are almost never 100% efficient hence, the problem becomes how much neutralization is necessary to elicit the desired effect. If the antisense oligonucleotide is targeted toward the mRNA for a particular transcription factor or splice form of a transcription factor, then it may be possible to knock down or reduce the expression of that particular protein. The result of such a knockdown will be a new balance of transcription factor subunits in the cell, probably resulting in alteration of the relative amounts of particular homo- and heterodimers. 

At present, the two-step theory is still accepted, but it leaves out the question of receptor location within the cell so as to be able to cover all members of a family. The receptor, in the absence of hormone, is found associated with other proteins (hsp90, p59, and perhaps others) and very weakly bound to cell structures (nuclear or cytoplasmatic). The arrival of hormones transforms the receptor, freeing it from other proteins, giving it a greater affinity for nuclear structures, and causing it to achieve an active state as a transcription factor (Beato et al. 1996 Beato 1989). The difference is that the receptors not... 

Alternative mRNA maturation is frequent in tumor tissue expressing ER. In some cases it would give rise to truncated receptors that would maintain the capacity to bind hormones but would have lost their capacity as a transcription factor. Additionally, truncated receptors would be produced that would lack the capacity to bind hormones but would conserve intact their capacity to interact with DNA. In this case, the truncated receptors can become tumorigenic by stimulating the proliferation of cells uncontrolled by hormones. These receptor variants have been the object of exhaustive study at the level of mRNA in tumors of the breast, mainly estrogen-dependent tumors (Clemons et al. 2001 Garcia et al. 1988 Palmieri et al. 2002), but tests for the existence of receptor protein with these characteristics have not corroborated the expectation created by their theoretical interest. 

---