Transcription factors protein phosphorylation

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. 

The presence of tumor necrosis factor a directly leads to apoptosis via interaction with the tumor necrosis factor receptor, one of a class of receptors referred to as death receptors. NF-kB, which must enter the nucleus to initiate apoptosis, is a transcription factor sequestered in the cytoplasm by inhibitor of kB (IkB). The binding of TNFa to its receptor leads to the ubiquitin-dependent proteolysis of IkB, allowing NF-kB to enter the nucleus. The activation of apoptosis results directly from the stimulation of NF-kB, a transcription factor whose phosphorylation is controlled by vanadium compounds. In a global gene expression study, it was found that diabetes increased the formation of IkB, whereas vanadium compound treatment lowered the production of this inhibitor [101]. The activation of the TNFR also activates the caspase proteins, a class of proteases that cleave proteins after specific aspartate residues. 

Fig. 11.1 Activation of MAPK pathway by Angll and ET-1 in VSMC. Stimulation of Angll and ET-1 receptors through Gq/n activation enhances the activity of PLCp. Activated PLC 3 converts PIP2 to IP3 and diacylglycerol (DAG). IP3 elevates the concentration of intracellular calcium and DAG activates PKC. PKC and/or Ca2+/calmodulin (CaM)-dependent protein kinases (CaMK) activate nonreceptor (NR) and/or receptor (R) protein tyrosine kinases. Activation of these components signals the stimulation of Ras/Raf/MEK/ERKl/2 and p70 s6k. ERK1/2 and p70 s6k are translocated to nucleus and regulate nuclear events by activating transcription factors through phosphorylation.

A major signalling pathway involves activation of a protein kinase that phosphorylates inhibitor kB proteins (IkBs) that normally inhibit the function of the nuclear transcription factor NFkB. Phosphorylation of IkB by the serine/threonine-specific IkB kinases (IKKs) leads to NFkB de-inhibition, nuclear translocation and expression of pro-inflammatory proteins such as inducible cyclooxygenase (iCOX) (which generates prostaglandins), inducible nitric oxide synthase (iNOS) (which generates vasodilatory and toxic free radicalgenerating NO) and pro-inflammatory cytokines. 

Figure 29.34 The CTD Coupling transcription to pre-mRNA processing. The transcription factor TFIIH phosphorylates the car boxy I-terminal domain (CTD) of RNA polymerase II, signaling the transition from transcription initiation to elongation. The phosphorylated CfD binds factors required for pre-mRNA capping, splicing, and polyadenyiation. These proteins are brought in close proximity lo their sites of action on the nascent pre-mRNA as it is transcribed during elongation.

Nonreceptor kinases, such as protein kinase A, also regulate transcription factors through phosphorylation. Many hormones generate the second messenger cAMP, which activates protein kinase A. Activated protein kinase A enters the nucleus and phosphorylates the transcription factor CREB (cAMP response element binding protein). CREB is constitutively bound to the DNA response element CRE (cAMP response element) and is activated by phosphorylation. Other hormone signaling pathways, such as the MAP kinase pathway, also phosphorylate CREB (as well as many other transcription factors). 

Many transcription factors, such as Myc and Fos, are proto-oncoproteins (the products of proto-oncogenes). MAP kinase, in addition to inducing myc and fos, also directly activates the AP-1 transcription factor through phosphorylation (see Fig. 18.5). AP-1 is a heterodimer formed by the protein products of the fos and jun families of proto-oncogenes. The targets of AP-1 activation are genes involved in... 

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... 

Also, phosphorylation of Akt results in activation of sterol regulatory-element binding protein 1 (SREBP1), a key transcription factor involved in regulation of lipogenic enzymes. In addition, some of the effects of insulin on cell proliferation and survival may be explained by an Akt-dependent inhibition of apoptosis through phosphorylation and inactivation of proa-poptotic proteins (e.g., BAD, Caspase 9). 

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