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PML/RARα fusion protein transactivates the tissue factor promoter through a GAGC-containing element without direct DNA association.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America . 2/23/2010, Vol. 107 Issue 8, p3716-3721. 6p. 4 Diagrams. - Publication Year :
- 2010
-
Abstract
- A severe coagulopathy is a life-threatening complication of acute promyelocytic leukemia (APL) and is ascribable mainly to the excessive levels of tissue factor (TF) in APL cells regulated in response to the promyelocytic leukemia/retinoic acid receptor α (PML/RARα) fusion protein. The underlying molecular mechanisms for this regulation remain ill-defined. With U937-PR9 cell lines stably expressing luciferase reporter gene under the control of different mutants of the TF promoter, both luciferase and ChIP data allowed the localization of the PML/RARα-responsive sequence in a previously undefined region of the TF promoter at position -230 to -242 devoid of known mammalian transcription factor binding sites. Within this sequence a GAGC motif (-235 to -238) was shown to be crucial because deletion or mutation of these nucleotides impaired both PML/RARα interaction and promoter transactivation. However, EMSA results showed that PML/RARα did not bind to DNA probes encompassing the -230 to -242 sequences, precluding a direct DNA association. Mutational experiments further suggest that the activator protein 1 (AP-1) sites of the TF promoter are dispensable for PML/RARα regulation. This study shows that PML/RARα transactivates the TF promoter through an indirect interaction with an element composed of a GAGC motif and the flanking nucleotides, independent of AP-1 binding. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ACUTE leukemia
*THROMBOPLASTIN
*DNA probes
*NUCLEOTIDES
*CELL lines
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 107
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 48439804
- Full Text :
- https://doi.org/10.1073/pnas.0915006107