Multiple Mixed Lineage Leukemia (MLL) Fusion Proteins Suppress p53-mediated Response to DNA Damage

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are often observed in acute leukemias of both myeloid and lymphocytic origin. Expression of MLL fusion proteins is known to induce malignant transformation of normal blood progenitors; however, molecular mechanisms of this pr...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-07, Vol.280 (26), p.24315-24321
Main Authors: Wiederschain, Dmitri, Kawai, Hidehiko, Shilatifard, Ali, Yuan, Zhi-Min
Format: Article
Language:English
Subjects:
Blotting, Western
Cell Line, Tumor
DNA Damage
DNA Primers - chemistry
Humans
Immunoprecipitation
Luciferases - metabolism
Models, Genetic
Myeloid-Lymphoid Leukemia Protein
Oncogene Proteins, Fusion - chemistry
Oncogene Proteins, Fusion - metabolism
Oncogene Proteins, Fusion - physiology
Plasmids - metabolism
Protein Structure, Tertiary
Radiation, Ionizing
Recombinant Fusion Proteins - chemistry
Retroviridae - genetics
Reverse Transcriptase Polymerase Chain Reaction
RNA - chemistry
Transcription, Genetic
Transcriptional Activation
Transfection
Translocation, Genetic
Tumor Suppressor Protein p53 - metabolism
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Summary:Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are often observed in acute leukemias of both myeloid and lymphocytic origin. Expression of MLL fusion proteins is known to induce malignant transformation of normal blood progenitors; however, molecular mechanisms of this process are still poorly understood. In this study we investigated the effect of several frequently detected MLL fusion proteins on p53 transcriptional activity. Our data show that MLL-AF9, MLL-AF10, MLL-ENL, and MLL-ELL substantially down-regulate p53-mediated induction of p21, MDM2, and Bax in response to DNA damage. Furthermore, we identify the reduction in p53 acetylation by p300 as a major mechanism of the inhibitory effect of MLL leukemic fusions. Our data suggest that abrogation of p53 functional activity can be a common feature of MLL fusion-mediated leukemogenesis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M412237200