Transcription factor c-myc

Another way to regulate caspases is by interaction with inhibitors. For example, fibroblasts that overexpress the growth-promoting transcription factor c-Myc die, because the caspase inhibitors (lAPs), inhibitors of apoptosis, are inactivated by phosphorylation. In Fig. 13.6 is shown how phosphorylation of a caspase inhibitor controls caspase activity and apoptosis. When cells are driven to proliferate by an overactive transcriptional activator, such as c-Myc, an unregulated active caspase, no longer restrained by the inhibitor, can overcome the effect of Bcl-2 and the cell will eventually die. Only when Bcl-2 is over-et ressed simultaneously with c-Myc, can cell death be prevented. Thus, Bcl-2 keeps the c-Myc signals in check.22,23... 

An important link exists between the pRb/E2F pathway, since ARF is one of the transcriptional targets of the E2F transcription factors. Furthermore, ARF is under transcriptional control by the transcription factor c-Myc, providing a link from c-Myc to the function of p53. 

The synthesis of the transcription factor C-myc is tightly regulated in normal cells, and it is expressed only during the S phase of the cell cycle. In a large number of tumor types, this regulated expression is lost, and c-myc becomes inappropriately expressed or overexpressed throughout the cell cycle, driving cells continuously to proliferation. 

The leucine zipper motif (see Chapter 3) was first recognized in the amino acid sequences of a yeast transcription factor GCN4, the mammalian transcription factor C/EBP, and three oncogene products, Fos, Jun and Myc, which also act as transcription factors. When the sequences of these proteins are plotted on a helical wheel, a remarkable pattern of leucine residues... 

Transcription factors Fos, Myc, Myb, p53, Hsp70 Hsp 70, protein kinase C Tyrosine aminotransferase HMGCoA reductase... 

Fig. 13.7 Processes influencing cyclin concentration. Upregulation of cyclin concentration occurrs mainly at the level of gene expression. Growth factors transduce signals via the MAPK pathway or other pathways to transcription factors (c-Jun, c-Myc) that activate e. g. cyclin D transcription. Phosphorylation of cyclins (e. g. cyclin E) can provide a signal for binding of the SCF complex and destruction by the ubiquitin-proteasome pathway. This phosphorylation can be induced by activated cyclin-CDK complexes. Cyclin destruction (e. g. cyclin B) can be also mediated by the anaphase promoting complex. Another mechanism for control of cyclin concentration uses changes in the subcellular distribution.

Immediate early genes, e.g., c-fos, c-jun, and c-myc, are the first genes whose expression is induced in cells after a growth stimulus. They encode transcription factors and induce the expression of other growth-related genes. 

G-CSF expression is controlled at both the transcriptional and posttranscrip-tional levels. A sequence of 300 nucleotides upstream of the initiation codon is conserved in both the murine and human genes, and this appears to contain three regulatory sites. G-CSF (and some other cytokine genes) may be constitutively transcribed by cells such as blood monocytes, fibroblasts and endothelial cells, but the mRNA may be short-lived (fi/2 < 15 min). The mRNA contains poly-AUUUA sequences in the untranslated region, and this motif is usually associated with mRNA instability. Indeed, such regions have also been identified in mRNA for GM-CSF, IL-1, IL-6, interferons, TNF, some growth factors, c-jun, c-fos, c-myc and c-myb. Upon the addi-... 

Fig. 11.4. Model of signal transduction via the IL-2 receptor. Binding of IL-2 to the IL-2 receptor initiates activation of the Janus kinases Jakl and Jak3. These phosphorylate tyrosine residues in the P-chain of the IL-2 receptor and in the transcription factor StatS. SH2 domains or PTB domains of adaptor proteins can bind to the Tyr phosphate residues of the P-chain and, as shown in the figure for the Shc/Grb2/Sos complex, can transmit a signal in the direction of the Ras pathway. The phosphorylated transcription factor StatS is translocated into the nucleus and activates the transcription of corresponding gene sections. Another signaling pathway starting from the activated IL-2 receptor involves the Lck and Syk tyrosine kinases (see Chapter 8). The pathway leads to induction of genes for transcription factors such as c-Myc and c-Fos.

The c-myc gene is presented as an example of overexpression of a transcription factor due to translocation. 

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