Transcription activator Nuclear localization

Sarge, K.D., Murphy, S.P., Morimoto, R.l. (1993). Activation of heat shock gene transcription by heat shock factor 1 involves oligomenzation, acquisition of DNA binding activity, and nuclear localization and can occur in the absence of stress. Mol. Cell. Biol. 13. 1392-1407. 

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]. 

Fig. 6.2. Proposed mechanisms of action of pure antiestrogens (fulvestrant). 1 Fulvestrant (ICI) binds to estrogen receptor (ER). 2 Fulvestrant binding to ER accelerates receptor degradation ( ER down-regulator ). 3 Rate of dimerization and nuclear localization of fulvestrant-ER complex is reduced. 4 Reduced binding of fulvestrant-ER to ERE. 5 No transcription of estrogen-responsive genes since AF-1 and AF-2 are inactive, no coactivators are recruited and the activity of RNA polymerase II is not activated (or inhibited) (Wakeling 2000)...

To investigate the effects of drugs on NFkB activation at the molecular level, the Electric Mobility Shift Assay (EMSA) is a useful read-out system. With this technique the nuclear localization of this transcription factor following activation and subsequent translocation can... 

Phosphorylation in the nuclear localization sequence of transcriptional activators can decide whether transport into the nucleus, and subsequent transcription activation, occms or not. 

In the case of intracellularly localized receptors the hormone must enter the cell in order to be able to interact with the receptor. The hormone usually penetrates the target cell by passive diffusion. The nuclear receptors can be classified as ligand-controlled transcription activators. The hormone acts as the activating hgand the activated receptor stimulates the transcriptional activity of genes which carry DNA elements specific for the receptor. 

The substrates of the MAP kinase pathway are very diverse and include both cytosolic and nuclear localized proteins. Phospholipase A2 and transcription factors of the Ets family are well characterized substrates of the ERK pathway. Phosphorylation of a Ser residue of phospholipase A2 by ERK proteins leads to activation of the lipase activity. Consequently, there is an increase in release of arachidonic acid and of lyso-phospholipids, which can act immediately as diffusible signal molecules or may represent first stages in the formation of second messenger molecules. 

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