Protein mitogens

Interferons [alFN, piFN and ylFN]. Interferons are a family of glycosylated proteins and are cytokines which are produced a few hours after cells have been infected with a virus. Interferons protect cells from viral infections and have antiviral activities at very low concentrations ( 3 x 10 M, less than 50 molecules are apparently sufficient to protect a single cell). Double stranded RNA are very efficient inducers of IFNs. There are three main types of IFNs. The aIFNs are synthesised in lymphocytes and the piFNs are formed in infected fibroblasts. The a and P families are fairly similar consisting of ca 166 to 169 amino acids. Although ylFNs are also small glycosylated proteins (ca 146 amino acids), they are different because they are not synthesised after viral infections but are produced by lymphocytes when stimulated by mitogens (agents that induced cell division). 

Bouaboula, M., Perrachon, S., Milligan, L., Canatt, X., Rinaldi-Carmona, M., Portier, M., Barth, F., Calandra, B., Pecceu, F., Lupker, J., Maffrand, J.-P., Le Fur, G., and Casellas, P. (1997). A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor. J. Biol. Ckem. 272 22330-22339. 

Fluorid ions stimulate bone formation by a direct mitogenic effect on osteoblasts mediated via protein kinase activation and other pathways. Further to these cellular effects, fluorides alter hydroxyapatite crystals in the bone matrix. In low doses, fluorides induce lamellar bone, while at higher doses abnormal woven bone with inferior quality is formed. The effect of fluorides on normal and abnormal (e.g. osteoporotic) bone therefore depends on the dose administered. 

Functionally, the Dl-like receptors (Dl, D5) are coupled to the G protein Gas and thus can stimulate adenylyl cyclase. The D2-like receptors (D2, D3, and D4) couple to pertussis toxin sensitive G proteins (Gai/0), and consequently inhibit adenylyl cyclase activity. While the Dl-like receptors almost exclusively signal through Gas-mediated activation of adenylyl cyclase, the D2-like receptors have been reported to modulate the activity of a plethora of signaling molecules and pathways. Many of these actions are mediated through the G(3y subunit. Some of these molecules and pathways include the calcium channels, potassium channels, sodium-hydrogen exchanger, arachidonic acid release, and mitogen-activated protein kinase pathways. 

Furthermore, PKCe is required for nerve growth factor-induced activation of mitogen-activated protein kinases and neurite outgrowth by ethanol. It is also required for ethanol-induced increases in N-type voltage-gated calcium channels in PC 12 neural cells. 

Stimulation of the insulin receptor results in the activation of two major pathways [3] (i) the mitogen-activated protein (MAP) kinase cascade (discussed in chapter MAP kinase cascade) and (ii) the phospha-tidylinositol 3-kinase (PI 3-kinase) pathway which has been extensively studied in the context of the metabolic responses to insulin (summarized in Table 1 and Fig. 2). 

MAP is the acronym for both, Microtubule Associated Protein and Mitogen Activated Protein. 

Mitogen activated protein kinase (MARK) cascades are three kinase modules activated by phosphorylation. The three kinase modules are composed of a MAPK, a MAPKK, and a MAPKKK. There are multiple members of each component of the MAPK cascade that are conserved from yeast to human. Activation of selective MAPK modules by specific stimuli regulates cell functions such as gene expression, adhesion, migration, differ entiation, and apoptosis. 

Widmann C, Gibson S, Jarpe MB et al (1999) Mitogen-activated protein kinase conservation of a three-kinase module from yeast to human. Physiol Rev 79 143-179... 

Pearson G, Robinson F, Gibson TB et al (2001) Mitogen-activated protein (MAP) kinase pathways regulation and physiological functions. Endocrine Rev 22 153-183... 

Mitogen activated protein kinase. MAP Kinase Cascade... 

Activation of Mi, M3, and M5 mAChRs does not only lead to the generation of IP3 followed by the mobilization of intracellular Ca2+, but also results in the stimulation of phospholipase A2, phospholipase D, and various tyrosine kinases. Similarly, M2 and M4 receptor activation does not only mediate the inhibition of adenylyl cyclase, but also induces other biochemical responses including augmentation of phospholipase A2 activity. Moreover, the stimulation of different mAChR subtypes is also linked to the activation of different classes of mitogen-activated protein kinases (MAP kinases), resulting in specific effects on gene expression and cell growth or differentiation. 

The OP group of receptois share common effector mechanisms. All receptois couple via pertussis toxin-sensitive Go and Gi proteins leading to (i) inhibition of adenylate cyclase (ii) reduction of Ca2+ currents via diverse Ca2+ channels (hi) activation of inward rectifying K+ channels. In addition, the majority of these receptors cause the activation of phospholipase A2 (PLA2), phospholipase C 3 (PLC 3), phospholipase D2 and of MAP (mitogen-activated protein) kinase (Table 3). 

KC706 stabilizes the inactive conformation of the mitogen-activated protein kinase p38a, a protein kinase involved in inflammatory reactions and cardiovascular functions. KC706 therefore holds the potential to treat conditions such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and cardiovascular disease. This compound is currently being tested in phase II clinical trials with patients suffering from rheumatoid arthritis. 

Ras activates a number of pathways among them is the mitogen-activated protein (MAP) kinases, which transmit signals downstream to other protein kinases and gene regulatory proteins... 

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