| ObjectiveGrowth factor receptor binding activates multiple intracellular pathways, the appropriate integration of these pathways in proliferation, differentiation, and growth arrest are crucial for the function of a cell. The final outcome of growth factor signaling is the result of complicated interplay between activated pathways and feedback loops, and it is also dependent on the amplitude and duration of the signals as well as type of cell involved. The fibroblast growth factors (FGFs) are a family of angiogenic factors that are potent mitogens for fibroblast and en-dothelial cells, and overexpression of the growth factor and its receptors have been implicated in transformation and malignant progression. Mitogenic signals are transmitted from the activated tyrosine kinase receptors through several known pathways. Triggering these pathways depends on direct protein - protein interactions, posttranslational modifications, and the induction of second messenger molecules. The synthesis of one class of such molecules involves the phosphorylation of phosphatidylinositol and its D - 4 - and D - 5 - phosphoryla-ted derivates in the D - 3 position, in a reaction catalyzed by the phosphatidylin-isitol 3 - kinase(PI 3 - kinase). More and more studies have shown that the PI 3 - kinase exhibits both lipid and protein kinase activities, and in many cell types, plays a critical role in mitogenic or other signaling.PKB is activated in response to activation by many different GFs, includingIGF-1, epidermal GF, basic fibroblast GF, insulin, interlukin -3, interlukin- 6, and macrophage - colony stimulating factor. PKB is the cellular homologueof the product of the v - akt oncogene and has three isoforms: PKBα, -β, and-晊. PKB|3 and PKB-y are overexpressed in ovarian, pancreatic, and breast cancer cells. Activation of three isoforms is similar in that phosphorylation of two sites, one in the activation domain and the other in the COOH - terminal hydro-phobic motif, are necessary for full activity. For PKBa, phosphorylation of T308 in the activation domain by PDK1 is dependent on the products of PIS - K, PIP2 and PIP3. PIP2 and PIP3bind to the pleckstrin homology domains of PKB and PDK1, which relieves steric hindrance, fully activates PDK1, and translocates PKB to the plasma membrane. The mechanism of S473 phophorylation is less clear. Kinase potentially responsible for S473 phosphorylation include PDK1, integrin - linked kinase, or an integrin - linked kinase - associated kinase, PKB itself or an as - yet uncharacterized PDK2. PKB activation may also be achieved through PIS - K independent means, either through phosphorylation of PKB by kinases such as PKA or CAMKK , or under conditions of cellular stress.Cell proliferation is ultimately controlled at the level of cell cycle. Under appropriate stimuli, cells exit quiescence (GO phase) and enter the cell cycle at Gl. Progression through the cell - cycle is dependent on the balance of positive and negative regulatory cell - cycle proteins. During each phase of the cell - cycle there is an increase in expression for specific cyclins, which bind to their catalytic partners, the cyclin - dependent kinases ( CDK). This results in the formation of active cyclin - CDK complexes, which are responsible for the phos-phorylation of the retinoblastoma protein as well as other substrates, an event required for G1/S transition and DNA synthesis. The D - cyclins bind CDK4 in G1, whereas cyclin E and CDK2 complex at Gl/S transition. Cyclin A is com-plexed with CDK2 during S phase. Cyclin -kinase inhibitors(CKI) negatively regulate the cell - cycle by inhibiting cyclin - CDK complexes. One family of CKI include p21WAF1 ( abbreviated as p21 in this manuscript) and p27ap1, and the N - termini of these CKI share homology, and can bind to and inhibit CDK. p21 cyclin kinase inhibitor is up - regulated in response to growth arresting and differantiation signals, and it mediates cell cycle arrest by inhibiting cdk activity. Besides inhibiting the cell cycle machinery, p21 also f...
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