scholarly journals Activation of Signal Transducer and Activator of Transcription 3 by Oncogenic RET/PTC (Rearranged in Transformation/Papillary Thyroid Carcinoma) Tyrosine Kinase: Roles in Specific Gene Regulation and Cellular Transformation

2003 ◽  
Vol 17 (6) ◽  
pp. 1155-1166 ◽  
Author(s):  
Jung Hwan Hwang ◽  
Dong Wook Kim ◽  
Jae Mi Suh ◽  
Ho Kim ◽  
Jung Hun Song ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Cellular Transformation ◽  
Specific Gene ◽  
Signal Transducer ◽  
Papillary Thyroid ◽  
Transcription 3

scholarly journals Tumor Suppressor LKB1 Inhibits Activation of Signal Transducer and Activator of Transcription 3 (STAT3) by Thyroid Oncogenic Tyrosine Kinase Rearranged in Transformation (RET)/Papillary Thyroid Carcinoma (PTC)

2007 ◽  
Vol 21 (12) ◽  
pp. 3039-3049 ◽  
Author(s):  
Dong Wook Kim ◽  
Hyo Kyun Chung ◽  
Ki Cheol Park ◽  
Jung Hwan Hwang ◽  
Young Suk Jo ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Tumor Suppressor ◽  
Thyroid Carcinoma ◽  
Malignant Tumors ◽  
Kinase Domain ◽  
Signal Transducer ◽  
Papillary Thyroid ◽  
Loss Of Function ◽  
Amino Acid Region ◽  
Transcription 3

Abstract The tumor suppressor LKB1 (STK11) is a cytoplasmic/nuclear serine/threonine kinase, defects in which cause Peutz-Jeghers syndrome (PJS) in humans and animals. Recent studies showed that loss of function of LKB1 is associated with sporadic forms of lung, pancreatic, and ovarian cancer. In cancer cells, LKB1 is inactivated by two mechanisms: mutations in its central kinase domain or complete loss of LKB1 expression. Inactivation of LKB1 is associated with progression of PJS and transformation of benign polyps into malignant tumors. This study examines the effect of LKB1 on regulation of STAT3 and expression of transcriptional targets of STAT3. The results show that LKB1 inhibits rearranged in transformation (RET)/papillary thyroid carcinoma (PTC)-dependent activation of signal transducer and activator of transcription 3 (STAT3), which is mediated by phosphorylation of STAT3 tyrosine 705 by RET/PTC. Suppression of STAT3 transactivation by LKB1 requires the kinase domain but not the kinase activity of LKB1. The centrally located kinase domain of LKB1 is an approximately 260-amino-acid region that binds to the linker domain of STAT3. Chromatin immunoprecipitation studies indicate that expression of LKB1 reduces the binding of STAT3 to its target promoters and suppresses STAT3-mediated expression of Cyclin D1, VEGF, and Bcl-xL. Knockdown of LKB1 by specific small interfering RNA led to an increase in STAT3 transactivation activity and promoted cell proliferation in the presence of RET/PTC. Thus, this study suggests that LKB1 suppresses tumor growth by inhibiting RET/PTC-dependent activation of oncogenic STAT3.

scholarly journals 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

2004 ◽  
Vol 18 (11) ◽  
pp. 2672-2684 ◽  
Author(s):  
Eun Suk Hwang ◽  
Dong Wook Kim ◽  
Jung Hwan Hwang ◽  
Hye Sook Jung ◽  
Jae Mi Suh ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Mhc Class Ii ◽  
Tyrosine Kinases ◽  
Class Ii ◽  
Hashimoto's Thyroiditis ◽  
Signal Transducer ◽  
Papillary Thyroid ◽  
Regulatory Factor ◽  
Class Ii Transactivator

Abstract 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-γresponsive 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-DRα) 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.

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