Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis.
Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3'-kinase, protein kinase C or Ca/calmodulin-dependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.
Timofeeva
O A
OA
Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
Plisov
S
S
Evseev
A A
AA
Peng
S
S
Jose-Kampfner
M
M
Lovvorn
H N
HN
Dome
J S
JS
Perantoni
A O
AO
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002648:Child; D049452:Green Fluorescent Proteins / Q000235:genetics; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D018832:Molecular Chaperones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D014162:Transfection; D009396:Wilms Tumor / Q000378:metabolism* / Q000473:pathology
D051017:Apoptosis Regulatory Proteins; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D010768:Phosphoserine; D047390:Casein Kinase II