Nuclear transcription

Finally, it has to be mentioned that LPA also has an intracellular target site, which is the nuclear transcription factor, peroxisome proliferator-activated receptor-y (PPARy). LPA competes for thiazolidinedione binding and activates PPARy-dependent gene transcription. Thereby, LPA induced neointima formation in a rat carotid artery model. 

RNA-editing is a posttranscriptional mechanism mediated by RNA editases, which results in a site-selective deamination of adenosine to inosine. This alters codons and splicing in nuclear transcripts and thereby alters the structure and function of proteins. 

Alternatively, one interesting drug delivery technique exploits the active transport of certain naturally-occurring and relatively small biomacromolecules across the cellular membrane. For instance, the nuclear transcription activator protein (Tat) from HIV type 1 (HlV-1) is a 101-amino acid protein that must interact with a 59-base RNA stem-loop structure, called the traus-activation region (Tar) at the 5 end of all nascent HlV-1 mRNA molecules, in order for the vims to replicate. HIV-Tat is actively transported across the cell membrane, and localizes to the nucleus [28]. It has been found that the arginine-rich Tar-binding region of the Tat protein, residues 49-57 (Tat+9 57), is primarily responsible for this translocation activity [29]. 

These agents activate PPAR-y a nuclear transcription factor important in fat cell differentiation and fatty acid metabolism. PPAR-yagonists enhance insulin sensitivity in muscle, liver, and fat tissues indirectly. Insulin must be present in significant quantities for these actions to occur. 

As was mentioned earlier, DAG activates protein kinase C, which phosphorylates transcription factors like NFjcB nuclear transcription factor. NFjcB forms a multisubunit complex with an inhibitory subunit which is phosphorylated by PKC. The complex disintegrates and what is released translocates to the nucleus and initiates gene transcription. NFjcB is a heterodimer, with two distinct DNA-binding subunits 50 kDa and 65 kDa, both being members of the Rel transcription factor family. These proteins have an important role in the signaling cascade of the cellular defense system, and activate numerous genes in response to pathogens or inflammatory cytokines. 

Manna SK, Sarkar S, Barr J, Wise K, Barrera EV, Jejelowo O, Rice-Ficht AC, Ramesh GT (2005) Single-walled carbon nanotube induces oxidative stress and activates nuclear transcription factor-kappa B in human keratinocytes. Nano Lett. 5 1676-1684. 

Shimohata T, Onodera O, Tsuji S (2000) Interaction of expanded polyglutamine stretches with nuclear transcription factors leads to aberrant transcriptional regulation in polyglutamine diseases. Neuropathology 20(4) 326-333... 

Finally, inappropriate expression of nuclear transcription factors can lead to cell transformation. For example, the products of he,fos and myc proto-oncogenes are transcription factors that regulate the expression of proteins that promote progression through the cell cycle. Levels of the Fos and Myc proteins are tightly regulated in normal cells. Uncontrolled expression of these proteins leads to cell proliferation. 

Transcription and translation are spatially separated events in eucaryotes. The product of nuclear transcription is pre-mRNA. In order to enable translation, the information contained within the pre-mRNA must be transported out of the nucleus and into the cytosol. The quantity of processed mRNA available for translation decides to a high degree how much protein is formed by de novo synthesis. 

Fig. 3.6. Principles of signal transduction by transmembrane receptors and nuclear receptors, a) transmembrane receptors receive the signal on the cell surface and convert it into an intracellular signal that can be passed on until it reaches the nucleus, b) In signal transduction via nuclear receptors the hormone enters the cell and binds the receptor either in the cytosol (R) or nucleus (R ). Nuclear receptors act as nuclear transcription factors that bind specific DNA elements (HRE hormone responsive element) found in the promotor region of regulated genes to control their transcription rate.

Fibrates function primarily as ligands for the nuclear transcription receptor, PPAR- . They transcriptionally up-regulate... 

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