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Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells

K Fair1, M Anderson, E Bulanova

  • 1Cancer Center, Medical Center, Loyola University-Chicago, Maywood, Illinois 60153.

Molecular and Cellular Biology
|April 21, 2001
PubMed

Insights

The PHD fingers of MLL and trx proteins mediate homodimerization and bind to Cyp33. This interaction in leukemia cells alters HOX gene expression, suggesting Cyp33 binding modulates MLL

Area of Science:

  • Molecular biology
  • Genetics
  • Biochemistry

Background:

  • The function of conserved PHD fingers in human MLL and Drosophila trx proteins remains largely unknown.
  • MLL is implicated in gene regulation, particularly in leukemia.
  • Nuclear cyclophilins, such as Cyp33, are involved in various cellular processes.

Purpose of the Study:

  • To elucidate the function of PHD fingers in MLL and trx proteins.
  • To investigate the interaction between MLL and Cyp33.
  • To determine the role of the MLL-Cyp33 interaction in gene regulation, specifically HOX gene expression in leukemia.

Main Methods:

  • In vitro and in vivo interaction studies to confirm MLL-Cyp33 binding.
  • Co-localization studies using microscopy in mammalian cells.
  • Overexpression of Cyp33 in leukemia cells and analysis of HOX gene expression.
  • Assessment of cyclosporine's effect on gene expression alterations.
  • Analysis of gene expression in cells with a mutant MLL protein lacking PHD fingers.

Main Results:

  • MLL and trx PHD fingers mediate homodimerization and MLL binding to nuclear cyclophilin Cyp33.
  • MLL and Cyp33 interact both in vitro and in vivo, localizing to specific nuclear subdomains.
  • Overexpression of Cyp33 in leukemia cells leads to altered expression of MLL-regulated HOX genes.
  • These HOX gene alterations are suppressed by cyclosporine and absent in MLL mutants lacking PHD fingers.

Conclusions:

  • The PHD fingers of MLL are crucial for its interaction with Cyp33.
  • The MLL-Cyp33 interaction plays a significant role in modulating MLL's regulation of HOX genes.
  • This interaction is a potential target for therapeutic intervention in MLL-associated leukemias.

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