HSPA1A is an important regulator of the stability and function of ZNF198 and its oncogenic derivative, ZNF198-FGFR1.
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.
Kasyapa
Chitta S
CS
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Kunapuli
Padmaja
P
Cowell
John K
JK
D001559:Benzhydryl Compounds / Q000494:pharmacology; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D050939:Gene Fusion; D015723:Gene Library; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D011233:Precipitin Tests; D011760:Pyrrolidinones / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D001559:Benzhydryl Compounds; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; C490786:HSPA1A protein, human; C410027:KNK 437; D011760:Pyrrolidinones; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C111777:ZMYM2 protein, human; D049452:Green Fluorescent Proteins; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1