| The canals of Hering and bile ductules in human liver contain hepatic progenitor cells that can differentiate towards the biliary and hepatocyte lineage. Its activation, proliferation, and differentiation has been observed under certain physiological conditions, mainly when the proliferation of existing hepatocytes has been inhibited followed by severe hepatic injury. The proliferation and differentiation of hepatic progenitor cells is referred to as 'activation' and this process occurs to a variable degree in almost all human liver diseases. However, it still remains unclear as to how these cells migrate into the damaged areas and how they begin their proliferation and differentiation into functioning hepatic cells. Several studies indicated that the requirement for selective and sustained expression of growth factors during the early stages of stem cell activation is highlighted . HGF also know as scatter factor, is a multifunctional cytokine possessing a wide spectrum of biological activities, such as proliferation, survival, cell scatter, tubular morphogenesis and anti-apoptosis. Several recent studies have also suggested that HGF acts as a survival factor. Evidence has also emerged that it protects epithelial, endothelial and carcinoma cells against apoptosis induced by cytotoxic drug, gamma radiation and ultraviolet light. A recent study using a rat model has shown that gene transfection of HGF can attenuate acute liver injury, these studies suggested that HGF may be serve as an endogenously produced protective factor. Signaltransduction pathways for HGF in the cells involve tyrosine phsphorylation of C-MET. As a result, a multi-functional docking site for adaptor molecules of C-terminal tail of the (-subunit become phosphorylated at the tyrosine residues on position Tyr1349 and Tyr 1356. Their phosphorylation leads to interaction of c-met with several cytoplasmic signal transducers, and subsequent activation of p21ras, p44/42 mitogen-activated protein kinase (MAPK), p38 mitogen-activated protein kinase (p38MAPK), c-JUN N-terminal kinase, and phosphatidylinositol 3-kinase (PI3K). The MAP kinase signaling pathways had been shown to play an important role in stimulating cell proliferation, differentiation, survival and growth. The activation of PI3K/Akt pathway has been shown to be responsible for cell survival and cell scattering induced by growth factors and oncogenes. Multiple pro-apoptotic and anti-apoptosis proteins have been shown to be modified by the activation of Akt. The phosphorylation of Stat-3 is required for triggering differentiation for branching morphogenesis.NF-κB is an important regulator of the expression of a number of genes involved in immune, inflammatory, and growth responses. In most cell types, NF-κB is present in the cytosol in an inactive form as a heterodimer , and bund to one of the NF-κB inhibitory proteins(IκB). Activators of NF-κB (cytokines, growth factors and viral trans-activators ) trigger phosphorylation of IκBα, resulting in its ubiquityination and degradation. The free NF- κB dimmer subsequently translocates into the nucleus and activates transcription of target genes. Phosphorylation of IκBα is carried out by the IκB kinase (IKK), which is activated by the NF- κB-inducing kinase (NIK) or by the mitogen-activated protein kinase MEKK1. NF- κB is considered a key mediator in cell survival and anti-apoptosis. MAPK and/or PI3K and its target the protein kinase Akt involved in NF- κB dependent regulation Several recent studies have also suggested that HGF activates the NF-κB signaling pathway to stimulate cell growth. Others have previous found that NF-κB plays an important role in the inhibition of TNF-mediated apoptosis in hepatocytes . On other hand, studies of HGF null mice indicate that HGF is essential inembryonic development. The major effect is severe reduction in size of liver, with dissociation of parenchyma cells showing signs of apoptosis. Beg et al also showed that p65 knockout mice have a liver phenotype due to massiv...
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