Regulation of signal transducer and activator of transcription 1 (STAT1) and STAT1-dependent genes by RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncogenic tyrosine kinases.
Chimeric RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncoproteins are constitutively active tyrosine kinases found in thyroid papillary carcinoma and nonneoplastic Hashimoto's thyroiditis. Although several proteins have been identified to be substrates of RET/PTC kinases, the pathogenic roles played by RET/PTC in malignant and benign thyroid diseases and the molecular mechanisms that are involved are not fully understood. We found that RET/PTC expression phosphorylates the Y701 residue of STAT1, a type II interferon (IFN)-responsive protein. RET/PTC-mediated signal transducer and activator of transcription 1 (STAT1) phosphorylation requires RET/PTC kinase activity to be intact but other tyrosine kinases, such as Janus kinases or c-Src, are not involved. RET/PTC-induced STAT1 transcriptional activation was not inhibited by suppressor of cytokine signaling-1 or -3, or protein inhibitors of activated STAT3 [(protein inhibitor of activated STAT (PIAS3)], but PIAS1 strongly repressed the RET/PTC-induced transcriptional activity of STAT1. RET/PTC-induced STAT1 activation caused IFN regulatory factor-1 expression. We found that STAT1 and IFN regulatory factor-1 cooperated to significantly increase transcription from type IV IFN-gamma responsive promoters of class II transactivator genes. Significantly, cells stably expressing RET/PTC expressed class II transactivator and showed enhanced de novo membrane expression of major histocompatibility complex (MHC) class II proteins. Furthermore, RET/PTC1-bearing papillary thyroid carcinoma cells strongly expressed MHC class II (human leukocyte-associated antigen-DR alpha) genes, whereas the surrounding normal tissues did not. Thus, RET/PTC is able to phosphorylate and activate STAT1. This may lead to enhanced MHC class II expression, which may explain why the tissues surrounding RET/PTC-positive cancers are infiltrated with lymphocytes. Such immune response-promoting activity of RET/PTC may also relate to the development of Hashimoto's thyroiditis.
Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Seoul National University College of Medicine, Seoul, Korea.
Eun Suk
ES
Hwang
Dong Wook
DW
Kim
Jung Hwan
JH
Hwang
Hye Sook
HS
Jung
Jae Mi
JM
Suh
Young Joo
YJ
Park
Hyo Kyun
HK
Chung
Jung Hun
JH
Song
Ki Cheol
KC
Park
Su Hyeon
SH
Park
Hwan-Jung
HJ
Yun
Jin Man
JM
Kim
Minho
M
Shong
D002291:Carcinoma, Papillary / Q000201:enzymology* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005802:Genes, MHC Class II / Q000235:genetics; D006684:HLA-DR Antigens / Q000032:analysis / Q000235:genetics; D006801:Humans; D050856:Interferon Regulatory Factor-1; D018813:Multiple Endocrine Neoplasia Type 2a / Q000378:metabolism; D018814:Multiple Endocrine Neoplasia Type 2b / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000502:physiology*; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D050828:Protein Inhibitors of Activated STAT; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000502:physiology; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; C106529:PIAS1 protein, human; D010750:Phosphoproteins; D050828:Protein Inhibitors of Activated STAT; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D015534:Trans-Activators; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human