MAP Kinase Cascade and the Control of Cell Proliferation

摘要: Reinitiation of DNA synthesis in resting cells is the result cooperation between multiple signalling pathways. For example, our work on mode action α-thrombin as a sole mitogen for Chinese hamster lung fibroblasts has demonstrated that stimulates phospholipases (PIP2-PLC, PC-PLD, PLA2) and inhibits adenylyl cyclase, implicating activation pertussis toxin-sensitive insensitive G proteins. In addition, these pathways synergize with receptor-activated tyrosine kinases (IGF-I, FGF). A striking observation synergism growth factors, detected at late stage replication, mirrored initially level stimulation so called ‘early mitogenic events’ (Na-H antiporter activation, S6 phosphorylation, early gene transcription). These results suggest existence common key step(s) integrating Here we substantiate notion MAP kinases, p42 mapk p44 , are indeed good candidates transmitting factor signals to nucleus. To investigate structure-function relationships, raised specific antibodies able discriminate both isoforms cloned expressed an epitope-tagged . Firstly, showed similarly activated display, response or serum, rapid, biphasic persistent pattern parallels dual phosphorylation threonine tyrosine. Synergistic mitogens α-thrombin/FGF serotonin/FGF) synergistically activate particularly second phase. Secondly, kinase associated instance, cytoplasmic GO-arrested rapidly translocates into nucleus factors. Thirdly, found overexpression wild type form no effect control. contrast, dead-kinase mutant (T192A Y194F) behaves dominant-negative mutant. It strongly inhibited endogenous led inhibition cell proliferation. We therefore conclude this ‘mitogenic cascade’: Raf-1 ⇒ seems operate cytosol obligatory factor-induced GO S-phase transition. predict constitutive forms either should induce oncogenic phenotype least fibroblasts.