In malignant myeloid cells expression of Daxx downregulates expression of p53 and of the inhibitors of apoptosis proteins.
The role of Daxx, in particular its ability to promote or hinder proliferation, still remains controversial. In order to elucidate the functional relevance of Daxx in malignant myelocytes, the erythroleukemia cell line HEL was stably transfected with a Daxx-expressing vector or with the respective Daxx-negative control vector. Assessing the molecular consequences of ectopic Daxx-expression, we present evidence that Daxx downregulates p53. Moreover, we demonstrate that Daxx overexpressing myelocytes downregulate the proapoptotic Bcl-2 family member Bax, while expression of antiapoptotic Bcl-2 is not influenced. Furthermore, expression of Daxx diminishes expression levels of the initiator-procaspase-8 and -10, and the executioner procaspase-7, whereas the procaspase-3, -6 and -9 remain unaltered. The altered protein levels of the caspases in Daxx overexpressing myelocytes are accompanied by a decrease of expression levels of the inhibitor of apoptosis proteins (IAPs) cIAP-1, -2 and survivin. Despite the described impact of Daxx expression on major molecules of the apoptotic cascade, expression of Daxx in neoplastic myelocytes does not impact on the rate of proliferation. Upon a proapoptotic stimulus such as serum withdrawal Daxx is unable to maintain its influence on expression levels of p53, Bax, IAPs and the procaspase-8, -10 and -7.
Boehrer
Simone
S
Department of Internal Medicine III, Hematology and Oncology, Johann Wolfgang Goethe-University Hospital, 60590 Frankfurt am Main, Germany.
Nowak
Daniel
D
Schaaf
Simone
S
Bergmann
Marion
M
Brieger
Angela
A
Hoelzer
Dieter
D
Mitrou
Paris S
PS
Weidmann
Eckhart
E
Chow
Kai Uwe
KU
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D053455:Caspase 10; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056970:Co-Repressor Proteins; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004792:Enzyme Precursors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D048868:Adaptor Proteins, Signal Transducing; C494826:BAX protein, human; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D016895:Culture Media, Serum-Free; C106985:DAXX protein, human; D004792:Enzyme Precursors; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C505520:CASP7 protein, human; C505530:CASP8 protein, human; D053455:Caspase 10; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human