Direct transcriptional regulation of MDM2 by Fli-1.
The Ets transcription factor, Fli-1, has been shown to play a pivotal role in the induction and progression of Friend Murine Leukemia Virus (F-MuLV)-induced erythroleukemia, with its overexpression leading to erythroblast survival, proliferation, and inhibition of terminal differentiation. P53 inactivation is an additional genetic alteration that occurs in late-stage leukemic progression associated with in vivo and in vitro immortalization. Since p53 protein expression levels are low, to undetectable, in primary erythroleukemic cells that express elevated levels of Fli-1, we investigated the potential regulation of p53 by Fli-1. We assessed whether the overexpression of Fli-1 could partially regulate p53 via modulation of its well-established regulator, MDM2. In this paper, we demonstrate that the promoter of MDM2 contains a consensus binding site for Fli-1 that is bound by this transcription factor in vitro and in vivo, resulting in MDM2 transcriptional regulation. We further substantiate these observations in vivo by demonstrating a positive correlation in the expression of Fli-1 and MDM2, and a negative correlation with p53 in leukemic tissues obtained from mice with Friend Disease. These observations depict a significant function of Fli-1 overexpression in the indirect control of p53, evidently capable of leading to an increasingly aggressive erythroleukemic clone in vivo.
Truong
Amandine H L
AH
Department of Medical Biophysics, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Ontario, Canada M4N 3M5.
Cervi
David
D
Lee
Jane
J
Ben-David
Yaacov
Y
D000818:Animals; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D005622:Friend murine leukemia virus; D005786:Gene Expression Regulation; D006801:Humans; D007942:Leukemia, Experimental; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2; D012192:Retroviridae Infections; D015534:Trans-Activators / Q000494:pharmacology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000494:pharmacology*; D014412:Tumor Virus Infections; D015854:Up-Regulation; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C497426:Fli1 protein, mouse; D009687:Nuclear Proteins; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2