Protein level modulation

Susceptibility to dmg-induced apoptosis correlates with differential modulation of Bad, Bcl-2 and Bc1-Xl protein levels. Cell Death and Differentiation 7 574-586. 

Fig. 10.1. Principle of signal transduction through intracellular protein kinase cascades. The intracellular protein kinase cascades are organized in modules composed in most cases of three proteinkinases and a scaffold protein. The modules process signals that are registered, integrated and passed on at the inner side of the cell membrane by central switching stations such as the Ras protein or the Rac protein. In the case of the MAP kinase pathway, the cascade includes at least three different protein kinases. Specific regulatory processes may take effect at every level of the cascade in addition, signals may be passed from the different protein kinases to other signaling pathways.

An important subgroup of MAP kinases has the transcription factor c-Jun as substrate. These kinases are known as c-Jun NH2 terminal kinases (INK) or, due to their activation by stress signals, as stress activated protein kinases (SAPK). The JNK/SAPK proteins are part of their own protein kinase module that conducts stress signals further at the transcription level, and this signaling pathway is therefore known as the JNK/ SAPK pathway. 

Many mechanisms have been found to contribute to desensitization. Some mechanisms function relatively slowly over the course of hours or days, and these typically involve transcriptional or translational changes in the receptor protein level, or its migration to the cell surface. Other mechanisms of desensitization occur quickly, within minutes. Rapid modulation of receptor function in desensitized cells may involve critical covalent modification of the receptor, especially by phosphorylation on specific amino acid residues, association of these receptors with other proteins, or changes in their subcellular location. 

The ppk mutant of P. aeruginosa was also deficient in type-IV pili-mediated twitching and in swarming motility (Rashid and Kornberg, 2000). Some suggestions on the molecular mechanisms of PolyP- PPK action in motility were made (Rashid and Kornberg, 2000). These included the possible role of PolyP in the phosphorylation of Che-Y-like proteins or modulation of the Ca2+ level (Rashid and Kornberg, 2000). 

There are other complex issues with regard to the assessment of safety pharmacology studies. With the oligonucleotide therapeutics that modulate the translation of mRNA to proteins, like antisense/siRNA, there is a lag between administration of the drug and the pharmacologic activity that is mediated by reduction in protein levels. This lag is related to the mechanism of action and how long it takes for a reduction in protein synthesis to be reflected in reduced protein levels. Because of this lag it is probably better to... 

Following cannabinoid binding, multiple signaling pathways can be activated Gij0jS-protein mediated modulation of adenylate cyclase and cAMP levels Ca2+ and K+ ion channel activation or activation of different intracellular enzymes/effectors (i.e., kinases, ceramide) in a non-G-protein dependent manner (Childers et al., 1993 Felder et al., 1995 Mackie et al., 1995 Prather et al., 2000 Sanchez et al., 2001). 

Opioid receptors are seven transmembrane G-protein coupled inhibitory receptors (Bockaert, 1991), although an association to excitatory G-proteins has also been reported (Varga et al., 2003). Intracellular signaling by these receptors involves the inhibition of adenylate cyclase with a subsequent decrease in cAMP levels (Surprenant et al., 1990), regulation of intracellular calcium levels, modulation of potassium channels (Williams et al., 2001), and control of MAP-kinase and ERK activity (Eitan et al., 2003 Varga et al., 2003). 

The list of examples detailed above is by no means exhaustive. Several additional examples of the structure-based control of translation, such as repressor protein binding sequences on the mRNA transcripts and ribozymes [39], are among others that could be listed. The intentions of this chapter are not to enumerate examples of how structural characteristics of mRNA influence its translation. What should be evident from the preceding discussion is that mRNA structure is a critical determinant of translation, and synthetic DNA technology offers the possibility to alter and probe the effects of mRNA sequence on its structure and the resulting translation efficiency. Further developments in this area will be immensely valuable to metabolic engineering as it will enable practitioners to fine-tune the fluxes of desired metabolic pathways through modulation of protein levels. 

Armstrong CM, Goldberg DE. An FKBP destabilization domain modulates protein levels in Plasmodium falciparum. Nat. Methods 2007 4 1007-1009. 

It interacts with activator and repressor proteins that modulate the rate of transcription initiation over a wide dynamic range. These proteins, which play a more prominent role in eukaryotes than in prokaryotes, are called transcrip-tion factors or trans-acting elements. Gene expression is controlled mainly at the level of transcription, as will be discussed in detail in Chapter 31. 

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