Bid-deficient hepatocytes manifested delayed and reduced serum-stimulated proliferation, which was corrected Lenvatinib by ionomycin or reconstitution of Bid, particularly an ER-targeted Bid. Finally, B cell lymphoma

2–associated X protein (Bax) could also be found in the ER-enriched membranes, and Bax deficiency caused the same proliferation defect. However, Bid/Bax double deletion in hepatocytes did not further augment the defect, which suggested that Bid and Bax worked by the same regulatory mechanism in [Ca2+]ER control. Conclusion: Bid regulates hepatocyte proliferation by positively affecting [Ca2+]ER homeostasis, and this could be important for liver regeneration and carcinogenesis. (HEPATOLOGY 2010) Hepatocytes are highly differentiated cells, GSK126 datasheet but they retain a remarkable ability to proliferate in response to acute or chronic injury.1, 2 In the best studied rodent model of hepatocyte proliferation in vivo, that is, regeneration after 70% partial hepatectomy, the liver returns to its original size within 1 week after the resection. Massive hepatocyte proliferation can be documented within 48 hours in a nearly synchronous fashion. A number of factors are responsible for this

proliferation burst, including hepatocyte growth factor (HGF), epidermal growth factor (EGF), and other growth-promoting agents.1, 2 An important effector of the growth signaling seems to be calcium, which is required for quiescent hepatocytes to enter the cell cycle.3, 4 At the protein level, the transition of the resting hepatocyte into the proliferating state (G0-G1 transition) is characterized by increased cyclin D1 expression.5, 6 Cyclin D1 expression is critically regulated by extracellular stimuli that control hepatocyte proliferation during liver regeneration and in culture.7 There are multiple regulatory mechanisms at each of these steps that affect hepatocyte proliferation, not all of which have been characterized,

particularly at the level of calcium signaling. The B cell lymphoma 2 (Bcl-2) family proteins are best characterized for their regulation of apoptosis by targeting from the mitochondria.8 This family can be divided into two groups: the antiapoptotic members, such as Bcl-2 and B cell lymphoma extra long (Bcl-xL), and the proapoptotic members, such as BH3-interacting domain death agonist (Bid) and B cell lymphoma 2–associated X protein (Bax). Intriguingly, in addition to their function in apoptosis regulation, some members of this family have been found to also affect cell proliferation. Lymphocytes from Bcl-2 transgenic mice exhibited delayed entry into the S phase after mitogen stimulation, whereas those from Bcl-2–deficient mice had accelerated cell cycle entry.