Abstract
The ZNF198/FGFR1 fusion kinase associated with an atypical myeloproliferative disease is constitutively activated and regulates several STAT transcription factors. We used oligonucleotide microarrays to compare the gene-expression profiles between HEK-293 cells that stably express either the ZNF198/FGFR1 chimeric protein or the wild-type ZNF198 gene. Expression of the plasminogen activator inhibitor-2 (PAI-2/SERPINB2) was highly increased in cells expressing the fusion gene. Western blot analysis demonstrated that HEK-293 cells do not express PAI-2 endogenously, but in ZNF198/ FGFR1-expressing cells 2 molecular forms of PAI-2, which were 47 kDa and 32 kDa, were expressed intracellularly, and a 60-kDa form was secreted. Similarly, expression of ZNF198/FGFR1 in BaF/3 mouse hematopoietic cells also induced the expression of the PAI-2 protein. Immunoprecipitation analysis revealed that both intracellular forms of PAI-2 bind to the ZNF198/FGFR1 kinase. Treatment of HEK-293 and BaF/3 cells with TNF-α in the presence of cycloheximide, induced apoptosis in both cases. In contrast, HEK-293 and BaF/3 cells expressing ZNF198/FGFR1 were resistant to TNF-α-induced apoptosis. These observations suggest that expression of the ZNF198/FGFR1 fusion gene is associated with specific PAI-2-mediated resistance to apoptosis which may contribute to the highly malignant nature of leukemic cells carrying this fusion kinase gene.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3693-3699 |
| Number of pages | 7 |
| Journal | Blood |
| Volume | 107 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 1 2006 |
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ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology
Cite this
Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease. / Kasyapa, Chitta S.; Kunapuli, Padmaja; Hawthorn, Lesleyann; Cowell, John K.
In: Blood, Vol. 107, No. 9, 01.05.2006, p. 3693-3699.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease
AU - Kasyapa, Chitta S.
AU - Kunapuli, Padmaja
AU - Hawthorn, Lesleyann
AU - Cowell, John K.
PY - 2006/5/1
Y1 - 2006/5/1
N2 - The ZNF198/FGFR1 fusion kinase associated with an atypical myeloproliferative disease is constitutively activated and regulates several STAT transcription factors. We used oligonucleotide microarrays to compare the gene-expression profiles between HEK-293 cells that stably express either the ZNF198/FGFR1 chimeric protein or the wild-type ZNF198 gene. Expression of the plasminogen activator inhibitor-2 (PAI-2/SERPINB2) was highly increased in cells expressing the fusion gene. Western blot analysis demonstrated that HEK-293 cells do not express PAI-2 endogenously, but in ZNF198/ FGFR1-expressing cells 2 molecular forms of PAI-2, which were 47 kDa and 32 kDa, were expressed intracellularly, and a 60-kDa form was secreted. Similarly, expression of ZNF198/FGFR1 in BaF/3 mouse hematopoietic cells also induced the expression of the PAI-2 protein. Immunoprecipitation analysis revealed that both intracellular forms of PAI-2 bind to the ZNF198/FGFR1 kinase. Treatment of HEK-293 and BaF/3 cells with TNF-α in the presence of cycloheximide, induced apoptosis in both cases. In contrast, HEK-293 and BaF/3 cells expressing ZNF198/FGFR1 were resistant to TNF-α-induced apoptosis. These observations suggest that expression of the ZNF198/FGFR1 fusion gene is associated with specific PAI-2-mediated resistance to apoptosis which may contribute to the highly malignant nature of leukemic cells carrying this fusion kinase gene.
AB - The ZNF198/FGFR1 fusion kinase associated with an atypical myeloproliferative disease is constitutively activated and regulates several STAT transcription factors. We used oligonucleotide microarrays to compare the gene-expression profiles between HEK-293 cells that stably express either the ZNF198/FGFR1 chimeric protein or the wild-type ZNF198 gene. Expression of the plasminogen activator inhibitor-2 (PAI-2/SERPINB2) was highly increased in cells expressing the fusion gene. Western blot analysis demonstrated that HEK-293 cells do not express PAI-2 endogenously, but in ZNF198/ FGFR1-expressing cells 2 molecular forms of PAI-2, which were 47 kDa and 32 kDa, were expressed intracellularly, and a 60-kDa form was secreted. Similarly, expression of ZNF198/FGFR1 in BaF/3 mouse hematopoietic cells also induced the expression of the PAI-2 protein. Immunoprecipitation analysis revealed that both intracellular forms of PAI-2 bind to the ZNF198/FGFR1 kinase. Treatment of HEK-293 and BaF/3 cells with TNF-α in the presence of cycloheximide, induced apoptosis in both cases. In contrast, HEK-293 and BaF/3 cells expressing ZNF198/FGFR1 were resistant to TNF-α-induced apoptosis. These observations suggest that expression of the ZNF198/FGFR1 fusion gene is associated with specific PAI-2-mediated resistance to apoptosis which may contribute to the highly malignant nature of leukemic cells carrying this fusion kinase gene.
UR - http://www.scopus.com/inward/record.url?scp=33646411478&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646411478&partnerID=8YFLogxK
U2 - 10.1182/blood-2005-04-1505
DO - 10.1182/blood-2005-04-1505
M3 - Article
C2 - 16410451
AN - SCOPUS:33646411478
VL - 107
SP - 3693
EP - 3699
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -