A new hepatocytic isoform of PLZF lacking the BTB domain interacts with ATP7B, the Wilson disease protein, and positively regulates ERK signal transduction

J Cell Biochem. 2006 Oct 15;99(3):719-34. doi: 10.1002/jcb.20980.


The promyelocytic leukemia zinc finger (PLZF) protein has been described as a transcriptional repressor of the BTB-domain/zinc-finger family, and shown to regulate the expression of Hox genes during embryogenesis and the expression of cyclin A in the cell cycle progression. Here, a 45-kDa isoform of PLZF without a BTB domain was identified via yeast two-hybrid screening using the C-terminal region of ATP7B as bait in our determination of the biological roles of the Wilson disease protein outside of its copper-binding domain. Our immunoprecipitation experiments showed that the hepatocytic isoform of PLZF could specifically interact with the C-terminal region of ATP7B. The immunostaining of HepG2 cells revealed that the ATP7B and PLZF proteins were apparently colocalized into the trans-Golgi complexes. It was also determined that disruption of PLZF expression in the HepG2 cells affected an attenuation of ERK activity in a dose-dependent manner. The hepatocytic activities of ERK kinase were found to be enhanced as the result of PLZF or ATP7B expression, but this enhancement was abrogated by the deletion of the C-terminal region of ATP7B. Furthermore, a transgenic Drosophila strain that ectopically expressed the hepatocytic deltaBTB-PLZF exhibited phenotypic changes in eye and wing development, and these alterations were fully recovered as the result of ATP7B expression, indicating the obvious in vivo interaction between the two proteins. Those PLZF-induced abnormalities were attributed to the enhancement of ERK signaling, as was shown by phenotypic reversions with loss-of-function mutations in ERK signal transduction in Drosophila. These data suggest the existence of a mechanism that regulates ERK signaling via the C-terminus of ATP7B and the ATP7B-interacting hepatocytic PLZF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Cell Line
  • Copper-Transporting ATPases
  • Drosophila melanogaster / anatomy & histology
  • Drosophila melanogaster / physiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Molecular Sequence Data
  • Photoreceptor Cells, Invertebrate / metabolism
  • Photoreceptor Cells, Invertebrate / ultrastructure
  • Promyelocytic Leukemia Zinc Finger Protein
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • Protein Structure, Tertiary
  • RNA Interference
  • Sequence Alignment
  • Two-Hybrid System Techniques
  • Zinc Fingers
  • trans-Golgi Network / metabolism
  • trans-Golgi Network / ultrastructure


  • Cation Transport Proteins
  • Kruppel-Like Transcription Factors
  • Promyelocytic Leukemia Zinc Finger Protein
  • Protein Isoforms
  • ZBTB16 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • Adenosine Triphosphatases
  • ATP7B protein, human
  • Copper-Transporting ATPases