Details

Autor(en) / Beteiligte

• Yan, Jinsong
• Wang, Kankan
• Dong, Leiming
• Liu, Hongchen
• Chen, Weiqin
• Xi, Wenda
• Ding, Qiulan
• Kieffer, Nelly
• Caen, Jacques P
• Chen, Saijuan
• Chen, Zhu
• Xi, Xiaodong

Titel

PML/RARα fusion protein transactivates the tissue factor promoter through a GAGC-containing element without direct DNA association

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2010, Vol.107 (8), p.3716-3721

Ort / Verlag

National Academy of Sciences

Erscheinungsjahr

2010

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.