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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; proliferation ; CELL ; Germany ; IN-VIVO ; liver ; PROTEIN ; DIFFERENTIATION ; MICE ; ACTIVATION ; MECHANISM ; FAMILY ; T cells ; MEMBERS ; SUSCEPTIBILITY ; antibody ; DELETION ; MOUSE ; RATES ; DAMAGE ; B-CELLS ; INJURY ; FAMILIES ; development ; FULMINANT HEPATIC-FAILURE ; HUMAN HEPATOCELLULAR-CARCINOMA ; MCL-1 ; MAINTENANCE ; GROWTH-FACTORS ; OCCURS ; 33 ; ANTI-FAS ; BCL-2 PROTEINS
    Abstract: Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. It interacts with proapoptotic Bcl-2 family members, thereby inhibiting mitochondrial activation and induction of apoptosis. Mcl-1 is essential for embryonal development and the maintenance of B cells, T cells, and hematopoietic stem cells. We have recently shown that induction of Mcl-1 by growth factors rescues primary human hepatocy-tes from CD95-mediated apoptosis. This prompted us to further analyze the relevance of Mcl-1 for hepatocellular homeostasis. Therefore, we generated a hepatocyte-specific Mcl-1 knockout mouse (Mcl-1(flox/flox)-AlbCre). Deletion of Mcl-1 in hepatocytes results in liver cell damage caused by spontaneous induction of apoptosis. Livers of Mcl-1(flox/flox)-AlbCre mice are smaller compared to control littermates, due to higher apoptosis rates. As a compensatory mechanism, proliferation of hepatocytes is enhanced in the absence of Mcl-1. Importantly, hepatic pericellular fibrosis occurs in Mcl-1 negative livers in response to chronic liver damage. Furthermore, Mcl-1(flox/flox)-AlbCre mice are more susceptible to hepatocellular damage induced by agonistic anti-CD95 antibodies or concanavalin A. Conclusion: The present study provides in vivo evidence that Mcl-1 is a crucial antiapoptotic factor for the liver, contributing to hepatocellular homeostasis and protecting hepatocytes from apoptosis induction. (HEPATOLOGY 2009;49:627-636.)
    Type of Publication: Journal article published
    PubMed ID: 19127517
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  • 2
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; IN-VIVO ; PATHWAY ; VIVO ; DEATH ; DISEASE ; HEPATOCELLULAR-CARCINOMA ; liver ; PROTEIN ; TUMORS ; MICE ; MECHANISM ; FAMILY ; MARKER ; CARCINOGENESIS ; DELETION ; hepatocellular carcinoma ; CELL-DEATH ; AGE ; DAMAGE ; REGULATOR ; MITOSIS ; Bcl-2 ; INJURY ; HUMAN CANCER ; SURVIVIN ; cell death ; CANCERS ; HOMEOSTASIS ; HUMAN HEPATOCELLULAR-CARCINOMA ; MCL-1 ; LIVER-REGENERATION
    Abstract: Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1(Delta hep)), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in 〉50% of Mcl-1(Delta hep) mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1(flox/wt) mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1(Delta hep) mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. Conclusion: This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases. (HEPATOLOGY 2010;51:1226-1236.)
    Type of Publication: Journal article published
    PubMed ID: 20099303
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; AGENTS ; carcinoma ; CELL ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; KINASE ; THERAPY ; DEATH ; PROTEIN ; TISSUE ; LINES ; LIGAND ; INDUCTION ; TISSUES ; CELL-LINES ; DOWN-REGULATION ; TYROSINE KINASE INHIBITOR ; 5-FLUOROURACIL ; antibodies ; antibody ; NO ; immunohistochemistry ; resistance ; colorectal cancer ; COLORECTAL-CANCER ; RATES ; CELL-LINE ; chemotherapy ; MODULATION ; PCR ; CANCER-CELLS ; OXALIPLATIN ; TRAIL ; protein expression ; EPIDERMAL-GROWTH-FACTOR ; DRUG-INDUCED APOPTOSIS ; AGENT ; RNA INTERFERENCE ; THERAPIES ; TRANSFECTION ; LEVEL ; methods ; death receptor ; irinotecan ; PEOPLE ; EXTENT ; KINASE INHIBITOR ; HUMAN HEPATOCELLULAR-CARCINOMA ; epidermal growth factor receptor ; GROWTH-FACTOR-RECEPTOR ; BCL-XL ; MCL-1 ; quantitative ; WORLD ; TARGETED THERAPY ; EGF ; SMALL-MOLECULE ; Myeloid cell ; colorectal carcinoma ; Bcl-x(L) ; COLON-CARCINOMA ; epidermal growth factor receptor 1 ; leukaemia-1
    Abstract: AIM: To explore the role of Bcl-x(L) and Myeloid cell leukaemia (Mcl)-1 for the apoptosis resistance of colorectal carcinoma (CRC) cells towards current treatment modalities. METHODS: Bcl-x(L) and Mcl-1 mRNA and protein expression were analyzed in CRC cell lines as well as human CRC tissue by Western blot, quantitative PCR and immunohistochemistry. Bcl-x(L) and Mcl-1 protein expression was knocked down or increased in CRC cell lines by applying specific siRNAs or expression plasmids, respectively. After modulation of protein expression, CRC cells were treated with chemotherapeutic agents, an antagonistic epidermal growth factor receptor (EGFR1) antibody, an EGFR1 tyrosine kinase inhibitor, or with the death receptor ligand TRAIL. Apoptosis induction and cell viability were analyzed. RESULTS: Here we show that in human CRC tissue and various CRC cell lines both Bcl-x(L) and Mcl-1 are expressed. Bcl-x(L) expression was higher in CRC tissue than in surrounding non-malignant tissue, both on protein and mRNA level. Mcl-1 mRNA expression was significantly lower in malignant tissues. However, protein expression was slightly higher. Viability rates of CRC cells were significantly decreased after knock down of Bcl-x(L) expression, and, to a lower extent, after knock down of Mcl-1 expression. Furthermore, cells with reduced Bcl-x(L) or Mcl-1 expression was more sensitive towards oxaliplatin- and irinotecan-induced apoptosis, and in the case of Bcl-x(L) also towards 5-FU-induced apoptosis. On the other hand, upregulation of Bcl-x(L) by transfection of an expression plasmid decreased chemotherapeutic drug-induced apoptosis. EGF treatment clearly induced Bcl-x(L) and Mcl-1 expression in CRC cells. Apoptosis induction upon EGFR1 blockage by cetuximab or PD168393 was increased by inhibiting Mcl-1 and Bcl-x(L) expression. More strikingly, CD95- and TRAIL-induced apoptosis was increased by Bcl-x(L) knock down. CONCLUSION: Our data suggest that Bcl-x(L) and, to a lower extent, Mcl-1, are important anti-apoptotic factors in CRC. Specific downregulation of Bcl-x(L) is a promising approach to sensitize CRC cells towards chemotherapy and targeted therapy. (C) 2008 The WJG Press. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18609706
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