BCR/ABL activates mdm2 mRNA translation via the La antigen.
In a BCR/ABL-expressing myeloid precursor cell line, p53 levels were markedly downmodulated. Expression of MDM2, the negative regulator of p53, was upregulated in a tyrosine kinase-dependent manner in growth factor-independent BCR/ABL-expressing cells, and in accelerated phase and blast crisis CML samples. Increased MDM2 expression was associated with enhanced mdm2 mRNA translation, which required the interaction of the La antigen with mdm2 5' UTR. Expression of MDM2 correlated with that of La and was suppressed by La siRNAs and by a dominant negative La mutant, which also enhanced the susceptibility to drug-induced apoptosis of BCR/ABL-transformed cells. By contrast, La overexpression led to increased MDM2 levels and enhanced resistance to apoptosis. Thus, La-dependent activation of mdm2 translation might represent an important molecular mechanism involved in BCR/ABL leukemogenesis.
Trotta
Rossana
R
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA 19107, USA.
Vignudelli
Tatiana
T
Candini
Olivia
O
Intine
Robert V
RV
Pecorari
Luisa
L
Guerzoni
Clara
C
Santilli
Giorgia
G
Byrom
Mike W
MW
Goldoni
Silvia
S
Ford
Lance P
LP
Caligiuri
Michael A
MA
Maraia
Richard J
RJ
Perrotti
Danilo
D
Calabretta
Bruno
B
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001324:Autoantigens; D015152:Blotting, Northern; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D051380:GRB2 Adaptor Protein; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D000097585:SS-B Antigen
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001324:Autoantigens; D016044:Fusion Proteins, bcr-abl; D051380:GRB2 Adaptor Protein; D006133:Growth Substances; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000097585:SS-B Antigen; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse