HSPA1A is an important regulator of the stability and function of ZNF198 and its oncogenic derivative, ZNF198-FGFR1

J Cell Biochem. 2007 Dec 1;102(5):1308-17. doi: 10.1002/jcb.21362.

Abstract

Mass spectroscopy analysis demonstrated that the HSPA1A protein is found in complex with the ZNF198 protein which is involved in a chromosome rearrangement with the FGFR1 gene in an atypical myeloproliferative disease. HSPA1A is a member of the HSP70 family of genes which has been shown to be inducible in a variety of circumstances. Exogenous expression of the ZNF198-FGFR1 fusion kinase gene as well as ZNF198 in a model cell system results in a large (>650-fold) increase in HSP70 mRNA levels. Using KNK437, a specific inhibitor of HSP70 transcription, we have demonstrated that an important function of HSPA1A is to stabilize the ZNF198 and ZNF198-FGFR1 proteins. In the absence of HSPA1A, specific functions of ZNF198-FGFR1 such as STAT3 phosphorylation is also lost. Treatment of cells with KNK437 in the presence of MG132, an inhibitor of proteasomal degradation of proteins, suggested that only the ZNF198-FGFR1 protein is subject to the proteasomal degradation pathway, while ZNF198 is not. These observations suggest an important role for HSPA1A in ZNF198 and ZNF198-FGFR1 mediated cellular function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Benzhydryl Compounds / pharmacology
  • Cell Line
  • Cloning, Molecular
  • DNA, Complementary
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Gene Fusion
  • Gene Library
  • Genetic Vectors
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HSP70 Heat-Shock Proteins / genetics*
  • HSP70 Heat-Shock Proteins / metabolism*
  • Humans
  • Kidney / cytology
  • Precipitin Tests
  • Pyrrolidinones / pharmacology
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Sequence Analysis, DNA
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transfection

Substances

  • Benzhydryl Compounds
  • DNA, Complementary
  • DNA-Binding Proteins
  • HSP70 Heat-Shock Proteins
  • HSPA1A protein, human
  • KNK 437
  • Pyrrolidinones
  • Recombinant Fusion Proteins
  • Transcription Factors
  • ZMYM2 protein, human
  • Green Fluorescent Proteins
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1