Bid/Bax

doubly deficient hepatocytes presented a proliferation defect equivalent to, but no more than, that seen in the single deletion cells, and this suggests that the two molecules likely work in the same pathway. Biochemically, Bid can activate Bax or inactivate Bcl-xL, and Bax can inactivate Bcl-xL; this all occurs via protein-protein interactions.15 It is thus conceivable that Bid and Bax may both regulate [Ca2+]ER in hepatocyte by antagonizing the effect of Bcl-xL to prevent the latter from stimulating the InsP3 receptor and thus lowering [Ca2+]ER. The deletion of bid or bax could free Bcl-xL to promote ER calcium release via enhanced InsP3 receptor activity. This biochemical mechanism

has been shown in the Selleckchem Cabozantinib apoptotic scenario26, 28, 29 but may need to be formally proved in future studies in the case of hepatocyte proliferation. The coupled regulation of the ER calcium level and hepatocyte proliferation by Bid suggests that ER calcium release is a critical step at which the Bcl-2 family proteins can exert their control on cell proliferation. A transient rise in intracellular calcium is perhaps universally required for cell proliferation in response to hormones, growth factors, and cytokines.24 Both HGF4 and EGF,3 FK506 clinical trial the two most important growth factors for hepatocytes, induce intracellular Ca2+ elevation in the early stage of the cell cycle. Ca2+ is required in both the extracellular space and the intracellular store for normal cell growth.24 The rise in intracellular calcium due to ER calcium release activates the calcium channel on the plasma membranes to allow the influx of extracellular calcium. Thus, depletion of intracellular Ca2+ stores with pharmacological agents such as TG can cause a profound alteration of cell proliferation and result in an accumulation of cells 3-oxoacyl-(acyl-carrier-protein) reductase in the quiescent state.23 Calcium signaling is required for exit from G030 and the proper expression of G1 cyclin (i.e., cyclin D1 and cyclin E).31, 32 We have shown here that in mouse hepatocytes, the expression of cyclin D1 and, to a lesser extent,

cyclin E is intimately coupled with the level of Bid expression and intracellular calcium level, and this supports the hypothesis that Bid regulates ER calcium release, which in turn affects the prompt expression of cyclin D1. The importance of cyclin D1 expression in hepatocyte proliferation has been well established.5-7 Cyclin D1 expression is sufficient to promote progression of hepatocytes through the G1 restriction point.5, 6 How calcium signaling leads to cyclin D1 expression and/or other cell proliferation events is not completely understood. Calmodulin (CaM) is the major intracellular receptor for Ca2+, and Ca2+/CaM is required for proliferation in both unicellular and multicellular eukaryotes.