Regulation of Hoxb2 by APL-associated PLZF protein

Sarah Ivins, Kieran Pemberton, Fabien Guidez, Louise Howell, Robb Krumlauf, Arthur Zelent

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The PLZF gene is translocated in a subset of all-transretinoic acid resistant acute promyelocytic leukaemia (APL) cases, encodes a DNA binding transcription factor and is expressed highly in haematopoietic progenitor cells as well-developing central nervous system (CNS). The spatially restricted and temporally dynamic pattern of PLZF expression in the developing CNS suggested that it might play a role in the circuitry regulating hindbrain segmentation. We have now identified a PLZF binding site (PLZF-RE) in an enhancer region of Hoxb2 that itself is required for directing high-level expression in rhombomers 3 and 5 of the developing hindbrain. The wild-type r3/r5 enhancer linked to a heterologous promoter was responsive to regulation by PLZF, and this activity was lost in variants containing a mutated PLZF-RE. Compared with the wild-type protein, the binding of the APL-associated reciprocal RARα-PLZF fusion to PLZF-RE was much stronger, suggesting that the N-terminal PLZF sequences missing from the fusion may play a role in the regulation of DNA binding. Consistent with this, the N-terminal POZ domain was required for cooperative binding of PLZF to a multimerized PLZF-RE. In the context of the r3/r5 enhancer, the PLZF-RE cooperated for PLZF binding with an additional A/T-rich motif positioned downstream of the PLZF-RE. This A/T motif was previously shown to be essential for the regulation of Hoxb2 expression in r3 and r5 in cooperation with another Krüppel-like zinc finger protein Krox 20. The presence of both the PLZF-RE and the A/T-rich motif was required for a maximal effect of PLZF on a heterologous promoter and was essential in vivo to direct the expression of a lacZ reporter in the chick neural tube. Hence, both PLZF and Krox20 cooperate with a common A/T motif in mediating in vivo activity of the Hoxb2 enhancer. Our findings indicate that Hoxb2 is a direct target for regulation by PLZF in the developing CNS and suggest that deregulation of Hox gene expression may contribute to APL pathogenesis.

Original languageEnglish (US)
Pages (from-to)3685-3697
Number of pages13
JournalOncogene
Volume22
Issue number24
DOIs
StatePublished - Jun 12 2003

Keywords

  • Fusion protein
  • Leukaemia
  • Repressor
  • Retinoic acid receptor
  • Transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Ivins, S., Pemberton, K., Guidez, F., Howell, L., Krumlauf, R., & Zelent, A. (2003). Regulation of Hoxb2 by APL-associated PLZF protein. Oncogene, 22(24), 3685-3697. https://doi.org/10.1038/sj.onc.1206328