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RESEARCH PRODUCT

Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes

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Apoptosis, or programmed cell death, regulates tissue development and homeostasis in multi-cellular organisms. Extrinsic or intrinsic death signals activate pro-apoptotic pathways, resulting in the activation of caspases and finally in cell death. An important event during apoptosis process is the permeabilization of the outer mitochondrial membrane (OMM). Integrity of the OMM is regulated by the Bcl-2 protein family, which is divided into three groups: anti-apoptotic members Bcl-2, Bcl-xL and myeloid cell leukemia-1 (Mcl-1), pro-apoptotic multidomain members Bax and Bak, and pro-apoptotic BH3-only proteins. Mitochondrial activation is regulated by selective interactions of Bcl-2 proteins via their Bcl-2 homology (BH) domains (1–4). Expression of Mcl-1 has been found to be induced in cells at various stages of differentiation, in response to specific growth, differentiation, and survival factors. The importance of Mcl-1 during differentiation has been pointed out in Mcl-1 knock-out mice, which die at an early stage of embryogenesis (5). In conditional Mcl-1 knockout models, hematopoietic stem cells as well as early-stage B or T cells die due to apoptosis induction (6, 7). Due to its anti-apoptotic properties, Mcl-1 is a potential proto-oncogene. Mcl-1 transgenic mice show an increased incidence of B cell lymphomas (8). In addition, enhanced expression of Mcl-1 is observed in a wide range of tumors, including hepatocellular carcinoma (HCC) (9, 10). To date, little is known about the role of Mcl-1 in non-transformed cells. Mcl-1 expression is indispensable for the survival of hematopoietic stem cells, early stage B and T cells (6, 7), and macrophages (11). We have recently shown that induction of Mcl-1 by hepatocyte growth factor (HGF) protects primary human hepatocytes from CD95 (APO-1/Fas)-induced apoptosis (12). This observation is in line with studies which have shown that Mcl-1 transgenic mice are rescued from fulminant hepatic failure induced by CD95 triggering (13). Therefore, we assume that Mcl-1 is an important anti-apoptotic factor for the liver. In this study, we generated hepatocyte-specific Mcl-1 knock-out mice. In the absence of Mcl-1, liver homeostasis is critically affected. Spontaneous induction of apoptosis is increased in Mcl-1 negative hepatocytes, resulting in profound liver damage and hepatic fibrosis. Furthermore, hepatocytes lacking Mcl-1 expression are more sensitive towards pro-apoptotic stimuli. Therefore, we conclude that Mcl-1 is a central anti-apoptotic factor for hepatocytes.